High Incidence of Invasive Fungal Infections in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation.
Authors: Ma Winnie , Warkentin Dawn , Yeung Janice , Shepherd John D , Mourad Yasser Abou , Smith Clayton , Song Kevin , Hogge Donna E. , Barnett Michael J , Nevill Thomas J. , Nantel Stephen H. , Toze Cynthia L. , Sutherland Heather J. , Forrest Donna L. , Narayanan Sujaatha , Power Maryse M 
Published: October 2019

Abstract
Abstract 1136
Poster Board I-158

Introduction
Invasive fungal infections (IFI) are associated with significant morbidity and mortality in hematopoietic stem cell transplant (HSCT) patients. Prophylaxis of high risk patient groups has become a key strategy in managing these infections, which are characteristically difficult to pre-emptively diagnose. The benefit of newer prophylactic agents depends in part on the local incidence of IFI in a population. This study was carried out to define the incidence of IFI in a cohort of HSCT patients treated by the Leukemia/Bone Marrow Transplant Program of British Columbia, to elucidate risk factors for IFI and to assess the efficacy of our current prophylaxis strategy.

Methods
Two hundred and forty-nine adult HSCT patients who underwent autologous or allogeneic transplantation between October 2006 and March 2008 were retrospectively evaluated. One hundred and eighty patients underwent high dose chemotherapy and autologous HSCT during this period. The indication for HSCT in this group was predominantly multiple myeloma (n=95; 53%) or non-Hodgkins lymphoma (n=59; 32.8%). Sixty-nine patients underwent allogeneic HSCT using a related sibling (n=46) or matched unrelated (n=23) donor. The predominant indication for allogeneic HSCT was acute leukemia/ myelodysplasia (48%), followed by non-Hodgkins lymphoma (25%) and chronic lymphocytic leukemia (12%). Patients enrolled in prophylaxis clinical trials or with previously documented IFI were excluded from analysis. Routine antifungal prophylaxis with low dose amphotericin B (10mg/m2/day) for inpatients and oral fluconazole (400mg/day) for outpatients was given during the neutropenic phase throughout the period of the study.

Results
The overall incidence of proven, probable or possible IFI was 2.2% (4/180) and 19% (13/69) in autologous and allogeneic HSCT groups, respectively. The median time to IFI in autologous HSCT recipients was 12.5 days (7-19) post transplantation. In allogeneic HSCT patients, a bimodal incidence of IFI was observed with the first peak occurring within the first 30 days of transplantation and a later peak after 100 days. Invasive aspergillosis (IA) was the predominant IFI encountered (82%); the remaining IFI were due to invasive candidiasis (IC). The incidence of IA was 1.7% (3/180) and 16% (11/69) in autologous and allogeneic HSCT patients. Mortality attributable to fungal infection was 18% (3/17) and all deaths were cases of IA occurring in the allogeneic HSCT group. Modification of antifungal prophylaxis occurred in 23% of patients. Indications for changes in prophylaxis included: initiation of empiric therapy for suspected infection (18%), change to an orally active agent to facilitate discharge from hospital (12%), nephrotoxicity (14%) or infusion reactions (2%). Patients who developed IFI were more likely to have received prolonged high-dose corticosteroid therapy (i.e. prednisone >7.5mg daily for 3 weeks or more) for graft-versus-host disease (82% in IFI vs. 24% in non-IFI, p<0.001). Patients who received alemtuzumab or fludarabine as part of the conditioning regimen were also more likely to develop IFI (23% in IFI vs. 1.3% in non-IFI, p<0.001) and (23% in IFI vs. 6% in non-IFI, p=0.005), respectively. IFI patients were more likely to have received total parenteral nutrition during the peritransplant course (47% in IFI vs. 18% non-IFI, p<0.001).

Conclusion
Invasive fungal infections occurred in 19% of allogeneic HSCT recipients with an attributable mortality of 18%. IFI is less concerning in autologous HSCT recipients, occurring in 2% of cases. The predominant infection of concern is invasive aspergillosis in our population. Patients should receive prophylaxis during the neutropenic phase following allogeneic HSCT; those who develop graft-versus-host disease requiring prolonged steroid therapy should be particularly targeted for antifungal prophylaxis with mould-active antifungal agents. The role of T cell suppression in conditioning therapy and the influence of TPN exposure on the incidence of IFI is an area which warrants further study in defining specific risk groups for costly and potentially toxic prophylactic therapy.

Disclosures
No relevant conflicts of interest to declare.