An Early CT-Diagnosis Based Treatment Strategy for Invasive Fungal Infection in Allogeneic Transplant Recipients Using Caspofungin First Line: An Effective Strategy with Low Mortality.
Authors: Dignan Fiona L , Evans Stephen O , Ethell Mark E , Shaw Bronwen E. , Riley Unell BG , Davies Faith , Treleaven Jennifer G. , Dearden Claire E. , Morgan Gareth J. , Potter Michael N 
Published: April 2020

Empirical antifungal therapy is the standard treatment in allogeneic transplant patients who have persistent febrile neutropenia. This approach can be associated with increased cost, toxicity and breakthrough infections. There are limited reports to date of strategies for the early diagnosis of invasive fungal infection (IFI). These include either invasive investigations or serum testing. (Oshima K et al, J Antimicrobial Chemother2007 Aug; 60(2): 350–5, Maertens J et al, Clin Infect Dis2005; 41:1242–50). To our knowledge, there are no reports to date of treatment strategies based only on high resolution computerised tomography (HRCT) scans.

We used a CT-diagnosis based treatment strategy for early invasive aspergillosis in 99 consecutive patients undergoing allogeneic transplantation over a two year time period. A retrospective review of the electronic patient record, notes and drug charts was undertaken in all patients receiving an allogeneic transplant in our unit from 1st January 2006 to 31st December 2007. The study protocol was approved by the Royal Marsden Hospital audit committee. Patients received primary antifungal prophylaxis with itraconazole or secondary prophylaxis with voriconazole from day + 1. Patients had a HRCT scan performed if they had antibiotic resistant fever for &gt; 72 hours. Parenteral antifungal treatment with caspofungin was commenced in patients with a positive HRCT result. Cavitation, air crescent sign and halo sign were classified as major changes. Nodules and new infiltrates including consolidation and effusions were classified as minor changes. Serum testing was not used due to the possibility of false positive results with tazobactampiperacillin antimicrobials and low sensitivity in patients receiving mould active azoles as prophylaxis.

Neutropenic fever developed in 89/99 patients (90%). Fifty-four percent (53/99) of patients developed antibiotic resistant fever for &gt; 72 hours and would have received parenteral antifungal treatment if an empiric strategy had been used. The HRCT-based strategy reduced the use of parenteral antifungal treatment to 17% of patients (17/99). Four of these patients had engrafted (absolute neutrophil count &gt;0.5x109 cells/L for 3 days) at time of commencing caspofungin following a period of persistent neutropenic fever. Fifteen patients had a positive HRCT scan and 2 were treated empirically until a HRCT could be performed. The remaining 36/53 patients (68%) did not receive antifungal treatment although they would have met criteria for standard empirical therapy. Our nonempiric strategy reduced the use of parenteral antifungal treatment from 54% to 17% of allogeneic transplant patients. These findings represent a 68% reduction in use of parenteral antifungal agents

Caspofungin (70mg once daily IV on day 1 and 50mg once daily IV thereafter) was given for a median of 13 days (3–34 days) and 11 patients responded to treatment. Six patients required second line antifungal therapy. Only one patient died from IFI after 100 days of follow-up. No patients had to stop caspofungin due to toxicity. Three of the 36 patients who did not receive initial antifungal treatment went on to receive empiric caspofungin within 100 days. One of these 3 patients died of enterococcal septicaemia. The other 2 patients recovered. None of this group had probable or proven IFI. During the extended follow-up period of 3–27 months (median 13 months) only 3/99 patients (3%) died of IFI.

These results suggest that this non-empiric strategy of parenteral antifungal treatment based on HRCT scanning is feasible and may help to reduce toxicity, cost and breakthrough infections associated with the use of antifungal agents. Caspofungin may be a useful first line agent in this setting. A randomised controlled trial is warranted to further evaluate these results.