Empirical Antifungal Treatment in Neutropenic Patients Stratified by Risk: Prospective Validation of an Algorithm Based on the D-index

Neutropenia is a major risk factor for invasive fungal infections, particularly those caused by moulds, such as Aspergillus spp., Fusarium spp. and the Zygomycetes. Among neutropenic patients, these invasive mould infections (IMI) occur almost exclusively in patients with profound neutropenia (<100 neutrophils/mm3) lasting more than 10-15 days [1-3]. Empiric antifungal therapy is considered standard of care in patients with persistent or recurrent fever and neutropenia. However using fever as the sole criterion for starting empiric therapy, a significant number of patients will receive antifungal therapy unnecessarily, particularly among recipients of fluconazole prophylaxis, because persistent fever in these patients is commonly due to various factors, such as uncontrolled occult bacterial infection, viral infection, drug fever and others [4].

An alternative to empiric antifungal therapy is the preemptive treatment. In this strategy, other markers (such as serology, radiology and clinical data) are added to persistent fever [5,6]. One problem of such strategy is that the biomarkers currently in use (galactomannan [GM], 1,3-beta-D-glucan and PCR) have high sensitivity. If one of these markers is used to trigger the start of antifungal therapy, still a considerable number of patients will use antifungal agents unnecessarily. However, a positive biomarker early in the course of neutropenia most likely represents a false-positive result. By contrast, a positive biomarker test late in the course of neutropenia is more likely to be a true positive. A problem is that no cutoff value of duration of neutropenia is validated to help clinicians to identify these 2 possibilities.

A clinical parameter that evaluated the dynamics of neutropenia, combining intensity and duration, could be a good tool to identify patients at high risk for IMI. This tool could be used to stratify patients, helping clinicians to select appropriate candidates for early antifungal therapy (empiric or preemptive) in persistently febrile neutropenic patients. We developed an index (called D-index) that uses data from white blood cell counts (WBC), and combines intensity and duration of neutropenia. This index was tested in patients with acute myeloid leukemia, and showed a good discriminatory performance in identifying patients with IMI and without IMI. A cutoff was derived, and showed good sensitivity, specificity and a very high negative predictive value (97 to 99%) [7]. The high negative predictive value of this index is very similar to that obtained with GM and 1,3-beta-D-glucan in febrile neutropenic patients [8,9]. With this regard, the D-index could be of help to assess the pre-test probability of IMI and help to interpret the results of positive serum GM and / or 1,3-beta-D-glucan: patients with low values of D-index would be best interpreted as having false-positive results of these tests. Similarly, positive biomarkers in the presence of a high D-index would be more likely to be true positives, since the combination of different tests may increase their positive predictive value.

This is a prospective cohort study. The study will be submitted to the IRB and written informed consent will be obtained from all participants.

Patients aged ≥ 18 years are eligible if they have acute leukemia, myelodysplasia or other underlying hematologic malignancy receiving chemotherapy with an expected duration of neutropenia (<500/mm3) >10 days. This includes allogeneic (but not autologous) hematopoietic stem cell transplantation. Patients with past history of IMI will be excluded, since for these patients secondary prophylaxis is advised.