Invasive Fungal Diseases Caused By Rare Pathogens in Large Cohort of Pediatric and Adult Patients after Hematopoietic Stem Cell Transplantation and Chemotherapy

Background. In the expanding population of immunocompromised patients rare fungi have emerged as important pathogens, causing invasive infections associated with high morbidity and mortality. The number of publications on the invasive fungal diseases caused by rare pathogens (rare IFD) after hematopoietic stem cell transplantation (HSCT) and chemotherapy is limited.

Patients and methods. We design the retrospective study in order to investigate the epidemiology of rare IFD in large cohort of patients after HSCT and chemotherapy for 11-year period. From 2008 to 2018 in R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation (CIC725) were performed 3209 HSCT including 2118 allogeneic (allo-HSCT) and 1037 autologous HSCT (auto-HSCT). During the observation period 41 probable and proven rare IFD (EORTC/MSG 2008 criteria) cases were diagnosed in children and adults with hematological malignances and non-malignant hematological diseases after allo-HSCT (n=30), auto-HSCT (n=2), and chemotherapy (n=9). The median age was 24 (2-59) y.o., males - 61%(n=25). The median follow up time for rare IFD cases was 3 months; for survivors - 30 months.

Results. Incidence of rare IFD in HSCT recipients was 1,3%, it was higher after allo-HSCT (1,4%) than auto-HSCT (0,2%) (p<0,002). In nine patients, this complication developed after CT and four of them proceed to allo-HSCT. The most frequent underlying diseases were acute lymphoblastic leukemia (32%) and acute myeloid leukemia (29%). The median time of onset of rare IFD after allo-HSCT was 104 (21-1057) days, auto-HSCT - 138 (60-216), after start of CT - 161 (79-189). Etiology of rare IFD was identified by culture in 61% cases: Rhizopus spp. - 44%, Paecilomyces spp. - 16%, Fuzarium spp. - 8%, Malassezia furfur - 8%, Trichosporon asahii - 4%, Scedosporium apiosperium - 4%, Scopulariopsis gracilis - 4%, Rhizomucor pusillus - 4%, mix rare IFD with Rhizopus spp. + Paecilomyces spp. - 4%, Paecilomyces spp. + Fuzarium spp. - 4%. 35% cases (mucormycosis) were diagnosed with microscopy. In 44% cases rare IFD developed after or in combination with invasive aspergillosis, and 2 patients had both preexisting invasive aspergillosis and co-infection with mucormycosis. The main site of infection were lungs (82%), the main clinical symptom - fever (95%). All patients were treated with antifungals: lipid amphotericin B - 32%, lipid amphotericin B + caspofungin - 23%, voriconazole - 15%, posaconazole - 12,5%, lipid amphotericin B + posaconazole - 10%, and echinocandins - 7,5%. Surgery was used in 10% patients. Overall survival at 12 weeks from the diagnosis of rare IFD was 51,2%. The 12-weeks overall survival was better in patients after CT and auto-HSCT (81%) than allo-HSCT (40%), p=0,025.

Conclusions. The incidence of rare IFD in HSCT recipients was 1,3% and depends on type of transplantation. Rare IFD was a late complication after chemotherapy and HSCT and usually developed after or in combination with invasive aspergillosis. Higher incidence and worst prognosis of rare IFD was observed in allo-HSCT recipients.