PS1276 EPIDEMIOLOGY AND CLINICAL OUTCOME OF FUNGAL INFECTIONS OF THE CENTRAL NERVOUS SYSTEM IN ALLOGENEIC STEM CELL TRANSPLANTATION RECIPIENTS
Authors: Facchin G. , Candoni A. , Busca A. , Lazzarotto D. , Cattaneo C. , Nadali G. , Klimko N. , Del Principe M.I. , Castagnola C. , Verga L. , Calore E. , Capelli D. , Perruccio K. , Melillo L. , Pagano L. 
Published: June 2019

Background:

Invasive Fungal Infections of the Central Nervous System (IFI‐CNS) are very rare and life threatening complications and no specific epidemiologic data are available in Allogeneic Hematopoietic Stem Cell Transplantation (Allo‐HSCT) recipients.

Aims:

We describe the incidence, clinical characteristics and outcome of IFI‐CNS detected, over a 7 years period, in 13 Allo‐HSCT Centers.

Methods:

Between January 2010 and December 2016, 3866 Allo‐HSCT were performed in 13 HSCT Centers; in this cohort of patients there were 24 consecutive diagnosis of IFI‐CNS with an incidence of 0,62%. The diagnosis was made by biopsy ± histological examination, serum or/and liquor biomarkers and radiological examination (CT ± MRI). All cases of IFI‐CNS were proven (58%) or probable (42%) according to the EORTC criteria.

Results:

The median age of patients was 39 years (range 12–63) and acute leukaemia (10 myeloid and 7 lymphoid) was the most common underlying haematologic disease (71%); 54% of patients (13/24) had severe neutropenia (granulocytes less than 500/mmc) at the onset of infection and there was a concomitant extra CNS involvement (mainly lung) in 75% of cases. Among the 24 patients with IFI‐CNS, 16 had received an Allo‐HSCT from unrelated donors, 4 from a HLA‐id family donor and 4 from a haploidentical donor. Of 14 proven cases 12 were caused by moulds (7 aspergillosis, 3 mucormycosis, 1 fusariosis, and 1 scedosporidiosis) and 2 by yeasts (1 cryptococcosis and 1 trichosporonosis). All the 10 probable infections were caused by Aspergillus spp. The fungal biomarkers (galattomannan and others) on cerebrospinal fluid were performed in 11/24 (46%) of cases and were positive in 73% (8/11). The brain diagnostic biopsy was performed in 8% of cases and a biopsy from other concomitant involved sites was performed in 21% of cases. All patients received antifungal therapy mainly with amphotericine (14/24–58%) or voriconazole (11/24–46%). A combination antifungal therapy was administered in 33% (8/24) of cases. The antifungal therapy was coupled with neurosurgical intervention only in 17% of cases. The overall response rate (ORR) to treatment was 38%. Median follow‐up of 24 patients with IFI‐CNS was 7 months (range 0,3–63) with a 12 months overall survival (OS) probability of 23% (Figure 1). The overall mortality was 75% (18/24) and the IFI‐SNC attributable mortality was 44% (8/18).

Summary/Conclusion:

a)Proven or Probable IFI‐CNS remains a very rare infectious complication after Allo‐HSCT with an incidence of 0,62% in this recent epidemiological survey. The most important causative agent remains Aspergillus sp and a concomitant extra CNS involvement (mainly lung) is very common (in 75% of the reported cases).

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b)The fungal biomarkers on cerebrospinal fluid, when performed, were highly informative (positive in 73% of our case series). This underlines that diagnostic lumbar puncture should be encouraged when we suspect an IFI‐CNS to confirm the diagnosis and to promptly start a targeted therapy.

c)The CNS biopsy and the surgical approach were performed in a minority of cases.

d)Despite the availability of a broad spectrum of antifungal drugs the ORR remains poor (38% in the present series) and the probability of OS at 12 months was only 23%. New drugs with better permeability in the CNS and less interactions with immunosuppressive agents (such as isavuconazole) and/or more aggressive diagnostic and therapeutic approach (combination antifungal therapy coupled with surgery) could improve the outcome of IFI‐CNS in Allo‐HSCT recipients.