Post-Engraftment Infections in Adult Patients Transplanted with Single Cord Blood Units Supported by Co-Infusion of Mobilized Purified Hematopoietic Stem Cells from a Third Party Donor.
Authors: Cabrera J. Rafael , Krsnik Isabel , Fores Rafael , Ruiz Elena , Bautista Guiomar , Navarro Belen , Gayoso Jorge , Gil Santiago , Regidor Carmen , Sanjuan Isabel , Ojeda Emilio , Garcia-Marco Jose A. , Fernandez Manuel N. 
Published: April 2020

Abstract
We have co-infused mobilized purified hematopoietic stem cells (HSC) from a third party donor to shorten neutropenia in single unit cord blood transplantation (CBT). We describe post-engraftment infectious complications in 33 consecutive adults with high-risk hematologic malignancies. Median age was 30 (range 16–59), 22 were male. Patients were conditioned with TBI or busulfan, fludarabine, cyclophosphamide and ATG. GVHD prophylaxis included CyA and steroids. Non-bacterial prophylaxis included fluconazol, acyclovir, trimethoprim-sulfamethoxazole and azithromycin or Fansidar (toxopositive cases). Median total infused CB cell dose was 2.26 x 107/kg (1.31–3.7). Pre-CBT toxoplasma serology was positive in 12, negative in 13 (4 received HSC from a seropositive donor) and unknown in 8 cases. Pre-CBT CMV serology was positive in 30 cases. Pre-CBT, 7 patients were HBsAb(+), HBsAg(−) and 1 HBsAg(+) HBsAb(−). ANC&gt;500/uL was achieved by 32/33, median time 10 days (9–36). Full CB chimerism was achieved in 32/33 cases. Most clinically significant infections occurred after ANC recovery (no major neutropenic infections).There were 34 episodes of CMV reactivation (3 patients developed CMV peumonitis and died &lt;+60).Three patients developed CNS toxoplasmosis (2 seropositive pre-CBT): 1 died as a result (day +70); 1 died of acute GVHD (+120); 1 is alive on Fansidar (+547). One patient had visceral leishmaniasis (day +180) (BM aspirate for FUO; alive on amphotericin, day +379). Seven patients developed hemorrhagic cystitis, 6 related to polyomavirus (PCR on urine): 4 resolved without specific treatment and 2 with treatment (cidofovir, leflunomide). One had asymptomatic viruria. Reappearance of HBsAg occurred in 3/7 of the HBsAb (+) HBsAg(–) patients after day 100: 1 asymptomatic, 1 acute hepatitis and 1 cirrhosis. A HBsAg(+) patient was transplanted on adefovir (no increase in the viral load or liver enzymes). Four late (≥120) episodes of HZV were seen. A 27-year-old native Spaniard died (day +39) of tripanosomiasis (BM aspirate for FUO, positive PCR). Activation of pre-CBT transfusion-related infection is suspected.
Short and long term results in adult CBT are improving. However we and others are reporting high incidence of post-engraftment unusual infections which seem related to delayed recovery of cell-mediated immunity. CMV, for which early diagnostic techniques and antiviral agents are available, heads the list. Our toxoplasma cases have prompted us to use prophylaxis in seropositive patients. HBV reactivation among HBsAb(+) HBsAg(−) patients raises the issue of prophylaxis during CBT versus close serological monitoring and pre-emptive therapy. Leishmaniasis is endemic among our city’s dogs, so we actively search for it in FUO (BM examination and culture). Polyomavirus can be found in the urine of up to 50% of BM recipients, viruria preceding symptoms. The value of prospective monitoring and the role of antivirals are unknown. Other unusual infections (as tripanosomiasis in our country) require high index of awareness and consideration in FUO protocols (BM, PB smears). Adult CB recipients are at very high risk of fastidious non-bacterial infections requiring wide pre-BMT screening, close analytical and clinical monitoring, prophylactic/preemptive strategies or early aggressive therapy and innovative immunotherapeutic approaches.