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. Disclosures Moiseev: MSD: Other: Travel grants; Pfizer: Other: Travel grants; Celgene: Consultancy, Other: Travel grants; BMS: Other: Travel grants; Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; Takeda: Other: Travel grants.

Central Nervous System Cryptococcal Infections in Non-HIV Infected Patients

Central nervous system (CNS) cryptococcosis in non-HIV infected patients affects solid organ transplant (SOT) recipients, patients with malignancy, rheumatic disorders, other immunosuppressive conditions and immunocompetent hosts. More recently described risks include the use of newer biologicals and recreational intravenous drug use. Disease is caused by Cryptococcus neoformans and Cryptococcus gattii species complex; C. gattii is endemic in several geographic regions and has caused outbreaks in North America. Major virulence determinants are the polysaccharide capsule, melanin and several ‘invasins’. Cryptococcal plb1, laccase and urease are essential for dissemination from lung to CNS and crossing the blood–brain barrier. Meningo-encephalitis is common but intracerebral infection or hydrocephalus also occur, and are relatively frequent in C. gattii infection. Complications include neurologic deficits, raised intracranial pressure (ICP) and disseminated disease. Diagnosis relies on culture, phenotypic identification methods, and cryptococcal antigen detection. Molecular methods can assist. Preferred induction antifungal therapy is a lipid amphotericin B formulation (amphotericin B deoxycholate may be used in non-transplant patients) plus 5-flucytosine for 2–6 weeks depending on host type followed by consolidation/maintenance therapy with fluconazole for 12 months or longer. Control of raised ICP is essential. Clinicians should be vigilant for immune reconstitution inflammatory syndrome.

Sporotrichosis in Renal Transplant Patients

The current report describes two renal transplant recipients who presented with sporotrichosis. In addition, the authors review the general aspects of sporotrichosis in renal transplant recipients reported in the literature. Sporotrichosis is a rare fungal infection in transplant patients and has been reported primarily in renal transplant recipients not treated with antifungal prophylaxis. Extracutaneous forms of sporotrichosis without skin manifestations and no previous history of traumatic injuries have been described in such patients and are difficult to diagnose. Renal transplant recipients with sporotrichosis described in the present report were successfully treated with antifungal therapy including amphotericin B deoxycholate, lipid amphotericin B formulations, fluconazole and itraconazole.

Comparison of Lipid Amphotericin B Preparations in Treating Murine Zygomycosis

ABSTRACT We compared the efficacies of liposomal amphotericin B (LAmB) and an amphotericin B lipid complex (ABLC) in diabetic ketoacidotic (DKA) or neutropenic mice with disseminated zygomycosis. ABLC was as effective as LAmB in neutropenic but not DKA mice. Low-dose ABLC was less effective than LAmB at reducing brain fungal burdens in both models.

Multicenter Evaluation of Risk Factors for Aspergillosis in Patients Treated with Lipid Amphotericin B Products: Outcomes, Drug Utilization Parameters, and Benchmarking

Purpose To evaluate the use of lipid amphotericin B products in relation to risk factors for aspergillosis and candidemia at the time therapy was initiated. Methods A single-group, concurrent, observational, multicenter study in hospitalized patients receiving a lipid amphotericin B product (Abelcet or AmBisome) was undertaken. The severity of illness, duration of therapy, length of hospital stay, microbiology, all-cause mortality, physician specialty, and clinical characteristics of each patient was recorded. Risk factors for aspergillosis and candidemia and process markers that might identify patients as candidates for lipid amphotericin B therapy were collected. Results One hundred eighty-six patients were enrolled in six US medical centers. One hundred four patients had positive fungal cultures; the majority of positive cultures were for Candida albicans (n = 40) or yeast (n = 27). Sixteen patients had positive cultures for Aspergillus. All patients receiving a lipid amphotericin B product had an overall statistically significantly greater number of risk factors for Candida vs Aspergillus infection. The mean (± SD) number of risk factors for Aspergillus was 2.46 ± 1.97 (range 0–10) and for Candida was 7.77 ± 3.14 (range 1–16) (P < 0.05). Risk factor assessment by medical service showed a statistically significantly larger number of Aspergillus risk factors in the bone marrow transplant (BMT) service compared with all other services (P < 0.05). Conclusions There were fewer documented risk factors for aspergillosis than candidemia in patients receiving a lipid amphotericin B product. Establishing drug usage protocols that include culture analysis, risk factor identification, high-risk medical services, and incorporation of drug use evaluation measures can guide the practitioner in selecting the appropriate therapy for their patients.