Empiric or Presumptive Anti-Aspergillus Treatments for Allogeneic Hematopoietic Stem Cell Transplant Recipients with Sustained Febrile Neutropenia.

Background: Although the onset of invasive pulmonary aspergillosis (IPA) after allogeneic hematopoietic stem cell transplantation (HSCT) was bimodal, IPA early after HSCT has become less frequent, partly due to the shortening of neutropenic periods by the use of peripheral blood stem cells or colony-stimulating factors. Therefore, the validity of empiric anti-Aspergillus treatments based on sustained febrile neutropenia according to the IDSA guideline should be re-evaluated.

Patients and Methods: We retrospectively reviewed the clinical records of 114 adult patients who underwent allogeneic HSCT between September 2002 and December 2005 in HEPA-filtered clean rooms at the University of Tokyo Hospital. Fluconazole at 200 mg/day was given as anti-Candida prophylaxis. In general, anti-Aspergillus agents were not started empirically, but presumptively started after the detection of positive Aspergillus antigen, positive beta-D-glucan, halo-sign on chest X-ray or CT-scan, and so on, associated with sustained febrile neutropenia. For the definition of early IPA, we employed proven or probable IPA according to the EORTC/MSG criteria that developed between the day of HSCT and seven days after engraftment.

Results: All but two who experienced early death showed neutrophil engraftment at a median of 16.5 days after HSCT. Although 15 patients developed IPA after HSCT, early IPA was observed only in 2 (1.8 %) patients. Among 73 patients who experienced sustained febrile neutropenia for more than 7 days before engraftment, we empirically started anti-Aspergillus agents in 13 patients a median of 9 days after the development of febrile neutropenia, whereas fluconazole was continued in 60 patients who had febrile neutropenia for 15 days in median. Four of the 60 patients received presumptive anti-Aspergillus therapy, one of whom developed probable IPA after the initiation of treatment. There was another patient who received anti-Aspergillus treatment only after the development of probable IPA because he showed no prior signs for presumptive therapy. There was no difference in the incidence of early IPA between patients who received empiric anti-Aspergillus therapy and those who did not (0% vs. 3.3%, P>0.99). The two patients who developed early probable IPA were successfully treated with anti-Aspergillus agents.

Conclusions: These findings throw doubt on the validity of empiric anti-Aspergillus treatments for allogeneic HSCT recipients with sustained febrile neutropenia, provided that they are treated in clean units with anti-Candida prophylaxis. A randomized controlled trial is warranted to compare empiric and presumptive anti-Aspergillus treatments for allogeneic HSCT recipients with sustained febrile neutropenia.