Anne Nihtinen

Human herpesvirus 6 antigenaemia in allogeneic stem cell transplant recipients: impact on clinical course and association with other beta‐herpesviruses

Human herpesvirus 6 (HHV‐6) antigenaemia was prospectively studied in 58 adult allogeneic stem cell transplant (SCT) recipients. Altogether 42 of 58 recipients (72%) demonstrated HHV‐6 specific antigens in peripheral blood mononuclear cells after SCT, 22 of 36 (61%) when the donor was a sibling and 20 of 22 (91%) when the donor was unrelated. The cumulative incidence of HHV‐6A, HHV‐6B, HHV‐7, and cytomegalovirus antigenaemia during the first 6u2003months after SCT was 33%, 62%, 44% and 63% respectively. The median day of the onset of each antigenaemia was +24, +4, +59, and +46 after SCT respectively. There were no clinical findings related to HHV‐6A and HHV‐7 antigenaemias. A rash was diagnosed in 10 of 38 (26%) HHV‐6B antigenaemia positive patients during the first month after SCT compared with one of 20 (5%) HHV‐6B negative patients. Of the HHV‐6B antigenaemia cases, six of 10 rashes were treated as acute graft‐versus‐host disease (GVHD) and four of 10 were considered to be of a viral origin. Fifteen patients had acute GVHD diagnosed. Acute GVHD manifested statistically significantly (Pu2003=u20030·034) earlier in the nine patients with HHV‐6B antigenaemia compared with the six patients who were HHV‐6B negative.

The utility of intensified environmental surveillance for pathogenic moulds in a stem cell transplantation ward during construction work to monitor the efficacy of HEPA filtration

A 12-week environmental study was performed to ensure that the patient rooms of an SCT ward with high-efficiency particulate air (HEPA) filtration remained uncontaminated by moulds during close-by construction work. The sampling included measuring the ventilation channel pressure, particle count measurements, air sampling, settled dust analysis and fungal cultures from the oral and nasal cavities of the patients. No changes in the air pressure occurred. Median particle counts in patient rooms were 63–420 particles/l. The mean particle count of the outside air was173u2009659 particles/l. Patient room air samples were negative for aspergilli in 32 of 33 cases. All samples of the outside air were positive for moulds. Aspergillus fumigatus was isolated at the beginning of excavation works at the construction area and in two of 33 dust samples from patient rooms. All 70 nasal samples were negative. Of 35 mouth samples, one sample was positive for A. niger in a patient with a previously diagnosed aspergillus infection. During a median follow-up of 214 days, no invasive aspergillus infections were diagnosed in the 55 patients treated during the construction period. In conclusion, the HEPA filters seemed to have performed well in preventing an aspergillosis outbreak.

Autologous bone marrow mononuclear cell transplantation in ischemic heart failure: A prospective, controlled, randomized, double-blind study of cell transplantation combined with coronary bypass

BACKGROUNDnBone marrow mononuclear cell (BMMC) transplantation for heart failure has shown inconsistent therapeutic efficacy.nnnMETHODSnWe enrolled 104 ischemic heart failure patients scheduled for coronary artery bypass surgery (CABG). After 4- to 12-week pharmacotherapy optimization, 39 patients with left ventricular ejection fraction (LVEF) of ≤45% received injections of BMMC or vehicle intra-operatively into the myocardial infarction border area in a randomized, double-blind manner.nnnRESULTSnThe median number of cells injected was 8.4 × 10(8) (interquartile range [IQR]: 5.2 × 10(8) to 13.5 × 10(8)). We measured LV function and myocardial scar size by magnetic resonance imaging (MRI), and viability by positron emission tomography (PET) and single-photon emission computed tomography (SPECT), pre-operatively and after 1-year follow-up. LVEF, the pre-defined primary end-point measure, improved by a median of 5.6% in the control group (IQR 0.2 to 10.1) and by 4.8% in the BMMC group (IQR -0.5 to 8.2) (p = 0.59). Wall thickening in injected segments rose by a median of 4.5% among controls (IQR -18.1 to 23.9) and by 5.5% in the BMMC group (IQR -6.6 to 26.5) (p = 0.68). Changes in viability by PET and SPECT did not differ between groups. Myocardial scar size by MRI in injected segments rose by a median of 5.1% among controls (IQR -3.3 to 10.8), but fell by 13.1% in the BMMC group (IQR -21.4 to -6.5) (p = 0.0002).nnnCONCLUSIONSnBMMC therapy combined with CABG failed to improve LV systolic function, or viability, despite reducing myocardial scar size.

Candidaemia in allogeneic stem cell transplant recipients: low risk without fluconazole prophylaxis

Summary:Invasive fungal infections (IFI) are common in allogeneic SCT recipients. We have reviewed our experience of IFI with special reference to candidaemia in 685 adult patients transplanted in 1983–2002. The donor was a matched sibling in 505 patients and an unrelated donor in 180 patients. A BM graft was used in 561 patients and a PB graft in 124 patients. Fluconazole prophylaxis was not used during the study period. Definite or probable IFI was observed in 60 patients (8.7%) with a dominance of Aspergillus infections (46 patients, incidence 6.7%). Candidaemia was found only in nine patients (1.3%). The causative agents were Candida albicans (n=8), C. krusei (n=2), and C. glabrata (n=1); in two patients, two causative agents were found. The median time to the diagnosis of candidaemia was 53 days (range 6–249 days) post transplant. Seven patients were neutropaenic at diagnosis, and four patients had experienced acute GVHD. All patients received antifungal therapy, but only one patient was cured. According to this study, candidaemia was a rare event in allogeneic SCT recipients. Thus, systematic prophylaxis against Candida infections might not be indicated. The prognosis of established infections is still poor due to comorbid conditions, notably GVHD.

Invasive Aspergillus infections in allo-SCT recipients: environmental sampling, nasal and oral colonization and galactomannan testing.

A study was performed to investigate the air quality of a haematopoietic SCT ward, colonization of the upper airways with Aspergillus spp. and the role of galactomannan (GM) ELISA testing in serum in the diagnosis of invasive aspergillosis (IA). In 102 allo-SCT recipients, two cases of IA (one proven and one probable) were seen. Of 2071 serum samples, 12 were positive, two in a patient with proven IA and 10 in patients without IA. Of the 2059 negative samples, 22 were taken from the patient with probable IA. Of the 245 environmental samples, 20 (8.2%) were positive for filamentous fungi. Aspergillus fumigatus was seen in 14 samples. A total of 657 oral and nasal swabs were taken. Seven nasal samples and one oral sample were positive for Aspergillus species (A. fumigatus 4, A. niger 4) in four patients, one of whom had probable IA. In summary, most environmental samples were negative, colonization of the oral and nasal cavities was rare and IA was diagnosed in only 2% of patients. The GM ELISA test remained negative in one of two patients with IA and does not seem useful in a population of patients with a low incidence of IA.

Genetic polymorphism related to monocyte-macrophage function is associated with graft-versus-host disease

Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III–IV acute GvHD and extensive chronic GvHD was assessed. The functional effects of the variants were determined using expression and cytokine quantitative trait locixa0(QTL) database analyses. Clear heterogeneity was observed in the associated markers between the two populations. Interestingly, the majority of markers, such as those annotated to IL1, IL23R, TLR9, TNF, and NOD2 genes, are related to the immunological response by monocytes-macrophages to microbes, a step that precedes GvHD as a result of intestinal lesions. Furthermore, cytokine QTL analysis showed that the GvHD-associated markers regulate IL1β, IFNγ, and IL6 responses. These results support a crucial role for the anti-microbial response in GvHD risk. Furthermore, despite apparent heterogeneity in the genetic markers associated with GvHD, it was possible to identify a biological pathway shared by most markers in both populations.

Prospective, randomized, double-blinded trial of bone marrow cell transplantation combined with coronary surgery — perioperative safety study

OBJECTIVESnWe present here a sub-study of our prospective, randomized, double-blinded trial of bone marrow mononuclear cell (BMMC) transplantation with coronary artery bypass surgery (CABG) (ClinicalTrials.gov Identifier: NCT00418418), evaluating our secondary end-point concerning hospital stay as well as perioperative morbidity. Injecting a substantial amount of biologically active cells into a diseased myocardium inspires concerns for safety, a concern overlooked in previous trials.nnnMETHODSnWe evaluated the immediate perioperative effects of intramyocardial injection of autologous BMMCs combined with CABG. In a randomized double-blinded manner, 39 patients received injections either of BMMCs (n = 20) or of vehicle medium (n = 19). The patients haemodynamics, arterial blood gases, systemic vein oxygen level, blood glucose, acid-base balance, lactate, haemoglobin, body temperature and diuresis, as well as medications needed, were recorded in the operating theatre and in the intensive care unit (ICU) every 4 h throughout the first postoperative 24 h.nnnRESULTSnNo dissimilarities in these parameters were detectable. In the ICU, the median need for adrenaline was 0.0086 µg/kg/min (first quartile 0.0000, third quartile 0.0204) for controls and 0.0090 µg/kg/min (0.0000, 0.0353) for BMMC patients (P = 0.757); for noradrenaline, 0.0586 µg/kg/min (0.0180, 0.0888) for controls and 0.0279 µg/kg/min (0.0145, 0.0780) for BMMC patients (P = 0.405). The median stay at the ICU was 2 days for both groups (1, 2 for controls; 1, 3 for BMMCs; P = 0.967). Within the first postoperative day, one control patient had an elevated level of creatine kinase-myocardial band fraction mass (CK-MBm) up to >100 µg/l; no BMMC patient showed elevated CK-MBm levels (P = 0.474).nnnCONCLUSIONSnBoth intramyocardial BMMC and placebo injections appear safe during surgery and immediate ICU stay after treatment of heart failure.

Long term impact of hyperleukocytosis in newly diagnosed acute myeloid leukemia patients undergoing allogeneic stem cell transplantation: An analysis from the acute leukemia working party of the EBMT

Up to 20% of acute myeloid leukemia (AML) patients present initially with hyperleukocytosis, placing them at increased risk for early mortality during induction. Yet, it is unknown whether hyperleukocytosis still retains prognostic value for AML patients undergoing hematopoietic stem cell transplantation (HSCT). Furthermore, it is unknown whether hyperleukocytosis holds prognostic significance when modern molecular markers such as FLT3‐ITD and NPM1 are accounted for. To determine whether hyperleukocytosis is an independent prognostic factor influencing outcome in transplanted AML patients we performed a retrospective analysis using the registry of the acute leukemia working party of the European Society of Blood and Marrow Transplantation. A cohort of 357 patients with hyperleukocytosis (159 patients with white blood count [WBC] 50 K‐100 K, 198 patients with WBCu2009≥u2009100 K) was compared to 918 patients without hyperleukocytosis. Patients with hyperleukocytosis were younger, had an increased rate of favorable risk cytogenetics, and more likely to be FLT3 and NPM1 mutated. In multivariate analysis, hyperleukocytosis was independently associated with increased relapse incidence (hazard ratio [HR] of 1.55, 95% confidence interval [CI], 1.14‐2.12; Pu2009=u2009.004), decreased leukemia‐free survival (HR of 1.38, 95% CI, 1.07‐1.78; Pu2009=u2009.013), and inferior overall survival (HR of 1.4, 95% CI, 1.07‐1.84; Pu2009=u2009.013). Hyperleukocytosis retains a significant prognostic role for AML patients undergoing HSCT.

Incidence, Risk Factors, and Long-term Outcome of Acute Leukemia Patients With Early Candidemia After Allogeneic Stem Cell Transplantation: A Study by the Acute Leukemia and Infectious Diseases Working Parties of European Society for Blood and Marrow Transplantation

BackgroundnThis study was performed to assess the incidence of and risk factors for Candida infection in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT) and the impact on long-term survival.nnnMethodsnWe performed an outcome analysis of 28542 acute leukemia patients who underwent HSCT from 2000 to 2012. There were 347 patients with candidemia by day 100 and 28195 without candidemia or any other type of Candida infection.nnnResultsnThe incidence of candidemia by day 100 was 1.2% and occurred at a median of 22 days after HSCT. Higher 100-day nonrelapse mortality (NRM; hazards ratio [HR], 3.0, P < .0001) and lower 100-day overall survival (OS; HR, 2.5, P < .0001) were observed in patients with candidemia. The case fatality rate by day 100 in patients with candidemia was 22% (76/347). Factors associated with candidemia occurrence were female gender, bone marrow or cord blood stem cell source, T-cell depletion, use of total body irradiation, and acute graft vs host disease. Among the patients alive at day 100, the 5-year NRM and OS after a median follow-up of 5.6 years (95% confidence interval, 5.5 - 5.7) for patients with and without candidemia were 22.5% vs 13.5%, P < .0001 and 45.6% vs. 53.4%, P = .0003, respectively. In multivariate analysis, the occurrence of a candidemia episode by day 100 was an independent risk factor for higher NRM (HR, 1.7, P = .001) and lower OS (HR, 1.4, P = .001).nnnConclusionsnThe early occurrence of candidemia after HSCT is still associated with higher NRM and lower short- and-long-term OS.

A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis: GVHD Prevention

In a previously published study, the authors randomized 108 adult patients with a malignant hematologic disorder undergoing allogeneic bone marrow transplantation from a human leukocyte antigen‐identical sibling to receive methylprednisolone (53 patients; MP+) or not to receive methylprednisolone (55 patients; MP‐) as a part of graft‐versus‐host disease (GVHD) prophylaxis. All patients received cyclosporine and methotrexate. The cumulative incidence of acute GVHD was found to be significantly lower among the patients given MP.