Diagnostic and clinical aspects of invasive fungal disease after allogeneic hematopoietic stem cell transplantation

Invasive fungal disease (IFD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). Effective prophylaxis has reduced the incidence of invasive candidiasis, but invasive mold infections (IMIs)—especially invasive aspergillosis (IA)— continue to be an important cause of non-relapse mortality. However, there are very few data regarding IFD and IMI after HSCT in the Nordic countries. The aim of this thesis work was to investigate epidemiological, diagnostic, and clinical aspects of IFD in HSCT recipients at Karolinska University Hospital, Huddinge. In paper I, 99 patients who received reduced-intensity conditioning (RIC) were followed with weekly fungal PCR during the first 100 days after HSCT. Patients with a positive fungal PCR result were randomized to either treatment with liposomal amphotericin B or no treatment. We found that a single positive PCR test was not associated with IFD, irrespective of treatment. The cumulative incidence rate of proven or probable IA during the first year after transplantation was 9%, and significant risk factors in a multivariate model were grades II–IV acute-graft-versus host disease (aGVHD), cytomegalovirus(CMV-) seronegative recipient with CMV-seropositive donor, and conditioning with alemtuzumab. In paper II, a possible influence of the intensity of the conditioning on pneumonia-related death was investigated. We found no significant differences in the cumulative incidence of pneumoniarelated death between patients receiving myeloablative conditioning (MAC) and those receiving RIC: early death ( 60 years of age, with 0–20 years as reference), grades II–IV aGVHD, treatment with MSCs, and transplantation with female donor to male recipient. In patients with grade II aGVHD, no IMIs were seen after onset of GVHD in 113 HSCTs performed in patients 40 years of age (p 40 years of age prophylaxis is indicated if there are signs of poor immune reconstitution. LIST OF SCIENTIFIC PAPERS I. Blennow O, Remberger M, Klingspor L, Omazic B, Fransson K, Ljungman P, Mattsson J, Ringden O. Randomized PCR-based therapy and risk factors for invasive fungal infection following reduced-intensity conditioning and hematopoietic SCT. Bone Marrow Transplantation 2010 Dec;45 (12):1710-8. II. Forslow U, Blennow O, LeBlanc K, Ringden O, Gustafsson B, Mattsson J, Remberger M. Treatment with mesenchymal stromal cells is a risk factor for pneumonia-related death after allogeneic hematopoietic stem cell transplantation. European Journal of Haematology 2012 Sep;89 (3):220-7. III. Blennow O, Eliasson E, Pettersson T, Pohanka A, Szakos A, El-Serafi I, Hassan M, Ringden O, Mattsson J. Posaconazole concentrations in human tissues after allogeneic stem cell transplantation. Antimicrobial Agents and Chemotherapy 2014 Aug;58 (8):4941-3. IV. Blennow O, Remberger S, Torlen J, Ringden O, Ljungman P, Mattsson J. Incidence and risk factors for invasive mold infections after allogeneic stem cell transplantation. Submitted manuscript. RELATED PUBLICATIONS NOT INCLUDED IN THE THESIS i. Blennow O, Mattsson J, Remberger M. Pre-engraftment blood stream infection is a risk factor for acute GVHD grades II-IV. Bone Marrow Transplantation 2013 Nov;48(12):1583-4. ii. Uhlin M, Wikell H, Sundin M, Blennow O, Maeurer M, Ringden O, Winiarski J, Ljungman P, Remberger M, Mattsson J. 2014. Risk factors for Epstein-Barr virusrelated post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Haematologica 2014 Feb;99(2):346-52. iii. Blennow O, Ljungman P, Sparrelid E, Mattsson J, Remberger M. 2014. Incidence, risk factors, and outcome of bloodstream infections during the preengraftment phase in 521 allogeneic hematopoietic stem cell transplantations. Transplant Infectious Diseases 2014 Feb;16(1):106-14. iv. Blennow O, Fjaertoft G, Winiarski J, Ljungman P, Mattsson J, Remberger M. 2014. Varicella-Zoster Reactivation after Allogeneic Stem Cell Transplantation without Routine Prophylaxis-The Incidence Remains High. Biology of Blood and Marrow Transplantantation 2014 Jun 7.