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

Sammanfattning: 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 pneumonia-related death between patients receiving myeloablative conditioning (MAC) and those receiving RIC: early death (< 100 days after HSCT) 2.8% vs. 2.1%, and overall death 8.2% vs. 10.5%. Etiology could be established in 40 of 60 patients (67%) who died from pneumonia, with proven or probable IMI in 19 patients (48% of patients with established etiology, 32% of all patients with pneumonia-related death). In the multivariate analyses, grades II–IV aGVHD, CMV infection, and treatment with mesenchymal stromal cells (MSCs) were factors associated with overall pneumonia-related death. In paper III, posaconazole tissue concentrations were examined in vivo. Tissue concentrations of posaconazole were analyzed in biopsies taken at autopsy of seven patients who received posaconazole prophylaxis, and they were compared with plasma concentrations in samples taken before death. Accumulation of posaconazole was found in heart, lung, kidney, and liver tissue, while concentrations in brain were approximately equal to the concentrations in plasma. The apparent tissue accumulation in vivo is in agreement with earlier in vitro findings and may explain the low incidence of breakthrough infections seen in prophylaxis trials despite low serum concentrations. In paper IV, incidence and risk factors for IMI were retrospectively investigated in 843 patients. The cumulative incidences of proven and probable IMI were 2.2% at day 100, 5.2% after 1 year, and 6.3% after 2 years. Factors significantly associated with a new IMI were older age (risk hazard 4.26 for 41–60 years of age and 9.0 for > 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, compared to 14 IMIs in 106 HSCTs (13.2%) in patients > 40 years of age (p < 0.001). Twelve of these 14 patients had signs of poor immune reconstitution