Intestinal mucositis as driver of false-positive beta-D-glucan levels in AML patients undergoing remission induction chemotherapy?
Beta-D-glucan (BDG) assays support diagnosis of invasive fungal disease (IFD) in patients with haematological malignancies, but specificity is limited and confirmatory testing is recommended. False-positive BDG results have been linked with, among others, certain antibiotics, blood products, and intestinal mucositis. Intestinal mucositis, measurable with plasma concentration of citrulline, causes mucosal damage and loss of intestinal wall integrity, potentially facilitating translocation of fungal constituents such as BDG into the bloodstream. However, its impact on BDG false-positivity has been seldom studied, with inconsistent results. Therefore, we aimed to assess the association between citrulline and BDG false-positivity in patients receiving intensive chemotherapy for acute myeloid leukaemia (AML).
Patients with AML receiving intensive chemotherapy were selected from a previously published randomized controlled trial comparing pre-emptive versus empirical antifungal therapy (1). Patients from the pre-emptive arm with ≥10 available plasma samples, collected twice weekly, were included. In this arm, participants received fluconazole prophylaxis, and switched to caspofungin only upon IFD evidence. Samples from patients with probable or proven IFD were excluded. The impact of mucositis on BDG false-positivity was analysed using univariate and multivariate logistic mixed-effects models including citrulline, adjusting for type of RI chemotherapy, age, sex, study day, CRP (as systemic inflammation marker), and comorbidities (cardiovascular, metabolic, autoimmune, pulmonary, endocrine, psychiatric), with patient-level random intercepts. Severe mucositis was defined as citrulline plasma concentration ≤10 µmol/L.
Ten patients developed probable or proven IFD and were excluded, resulting in 70 included patients with 882 plasma samples. Of these, 44 (5%) were BDG false-positive. Median citrulline concentrations were similar in false-positive versus true-negative samples (11.4 µmol/L vs. 13.3 µmol/L, p = 0.86). Among samples collected during severe mucositis, 16/257 (6.2%) were false-positive, compared to 28/581 (4.8%) in samples without severe mucositis (p = 0.74). At the patient level, 15/59 (25.4%) who had experienced severe mucositis had ≥1 false-positive result, versus 5/11 (45.4%) without severe mucositis (p = 0.07). Multivariate analysis also showed no significant association between citrulline concentration and BDG false-positivity. However, higher CRP and time since enrolment were independently associated with increased odds of false-positivity (OR 1.57 per log-unit CRP, p = 0.02; OR 1.04 per day, p = 0.005).
BDG false-positivity among patients with AML receiving RI chemotherapy was associated with systemic inflammation and time since study enrolment, but not with intestinal mucositis. Whether systemic inflammation promotes the BDG accumulation in the bloodstream, circulating BDG contributes to inflammatory activation, or both are driven by an underlying factor is unclear and should be investigated further. These findings suggest that other factors, such as administration of antibiotics or blood products, may be more prominent causes of BDG false-positivity.