Transfusion efficacy of apheresis platelet concentrates irradiated at the day of transfusion is significantly superior compared to platelets irradiated in advance.

BACKGROUND Gamma irradiation is currently the standard care to avoid transfusion-associated graft-versus-host disease. Guidelines on gamma irradiation of blood components state that platelets (PLTs) can be irradiated at any stage in their 5-day storage and can thereafter be stored up to their normal shelf life of 5 days after collection. In this study, we explored whether the timing of irradiation has an effect on transfusion efficacy of apheresis PLT concentrates (APCs). METHODS Based on the 1-hour percent PLT recovery (PPR1h), transfusion efficacy of 1,000 eligible APCs transfused to 144 children were evaluated retrospectively. PPR1h was compared in transfused APCs irradiated at the day of transfusion and APCs irradiated in advance. RESULTS In univariate analysis, transfusion efficacy of APCs irradiated in advance was significantly lower than that of APCs irradiated at the day of transfusion (mean PPR1h 27.7 vs. 35.0%; p = 0.007). This was confirmed in multivariate analysis (p = 0.030). Compared to non-irradiated APCs, transfusion efficacy of APCs irradiated at the day of transfusion was not significantly inferior (mean difference -2.8%; 95% CI -6.1 to 0.5%; p = 0.092), but APCs irradiated in advance were clearly less efficient (mean difference -8.1%; 95% CI -12.2 to -4.0%; p < 0.001). CONCLUSION Our data strongly support that APCs should not be irradiated in advance, 1.e., ≥24 h before transfusion.

Abacavir induced T cell reactivity from drug naïve individuals shares features of allo-immune responses.

Abacavir hypersensitivity is a severe hypersensitivity reaction which occurs exclusively in carriers of the HLA-B*57∶01 allele. In vitro culture of PBMC with abacavir results in the outgrowth of abacavir-reacting CD8+ T cells, which release IFNγ and are cytotoxic. How this immune response is induced and what is recognized by these T cells is still a matter of debate. We analyzed the conditions required to develop an abacavir-dependent T cell response in vitro. The abacavir reactivity was independent of co-stimulatory signals, as neither DC maturation nor release of inflammatory cytokines were observed upon abacavir exposure. Abacavir induced T cells arose in the absence of professional APC and stemmed from naïve and memory compartments. These features are reminiscent of allo-reactivity. Screening for allo-reactivity revealed that about 5% of generated T cell clones (n = 136) from three donors were allo-reactive exclusively to the related HLA-B*58∶01. The addition of peptides which can bind to the HLA-B*57∶01-abacavir complex and to HLA-B*58∶01 during the induction phase increased the proportion of HLA-B*58∶01 allo-reactive T cell clones from 5% to 42%. In conclusion, abacavir can alter the HLA-B*57∶01-peptide complex in a way that mimics an allo-allele ('altered self-allele') and create the potential for robust T cell responses.

A Simple Guideline Reduces the Need for Red Blood Cell Transfusions in Swiss Hospitals: A Prospective, Multicentre, Before-and-After Study in Elective Hip and Knee Replacement

INTRODUCTION Optimising the use of blood has become a core task of transfusion medicine. Because no general guidelines are available in Switzerland, we analysed the effects of the introduction of a guideline on red blood cell (RBC) transfusion for elective orthopaedic surgery. METHODS Prospective, multicentre, before-and-after study comparing the use of RBCs in adult elective hip or knee replacement before and after the implementation of a guideline in 10 Swiss hospitals, developed together with all participants. RESULTS We included 2,134 patients, 1,238 in 7 months before, 896 in 6 months after intervention. 57 (34 or 2.7% before, 23 or 2.6% after) were lost before follow-up visit. The mean number of transfused RBC units decreased from 0.5 to 0.4 per patient (0.1, 95% CI 0.08-0.2; p = 0.014), the proportion of transfused patients from 20.9% to 16.9% (4%, 95% C.I. 0.7-7.4%; p = 0.02), and the pre-transfusion haemoglobin from 82.6 to 78.2 g/l (4.4 g/l, 95% C. I. 2.15-6.62 g/l, p < 0.001). We did not observe any statistically significant changes in in-hospital mortality (0.4% vs. 0%) and morbidity (4.1% vs. 4.0%), median hospital length of stay (9 vs. 9 days), follow-up mortality (0.4% vs. 0.2%) and follow-up morbidity (6.9% vs. 6.0%). CONCLUSIONS The introduction of a simple transfusion guideline reduces and standardises the use of RBCs by decreasing the haemoglobin transfusion trigger, without negative effects on the patient outcome. Local support, training, and monitoring of the effects are requirements for programmes optimising the use of blood.

Implementation of a mandatory donor RHD screening in Switzerland

Starting in 2013, blood donors must be tested at least using: (1) one monoclonal anti-D and one anti-CDE (alternatively full RhCcEe phenotyping), and (2) all RhD negative donors must be tested for RHD exons 5 and 10 plus one further exonic, or intronic RHD specificity, according to the guidelines of the Blood Transfusion Service of the Swiss Red Cross (BTS SRC). In 2012 an adequate stock of RHD screened donors was built. Of all 25,370 RhD negative Swiss donors tested in 2012, 20,015 tested at BTS Berne and 5355 at BTS Zürich, showed 120 (0.47%) RHD positivity. Thirty-seven (0.15%) had to be redefined as RhD positive. Routine molecular RHD screening is reliable, rapid and cost-effective and provides safer RBC units in Switzerland.

Oxypurinol directly and immediately activates the drug-specific T cells via the preferential use of HLA-B*58:01

Allopurinol (ALP) hypersensitivity is a major cause of severe cutaneous adverse reactions and is strongly associated with the HLA-B*58:01 allele. However, it can occur in the absence of this allele with identical clinical manifestations. The immune mechanism of ALP-induced severe cutaneous adverse reactions is poorly understood, and the T cell-reactivity pattern in patients with or without the HLA-B*58:01 allele is not known. To understand the interactions among the drug, HLA, and TCR, we generated T cell lines that react to ALP or its metabolite oxypurinol (OXP) from HLA-B*58:01(+) and HLA-B*58:01(-) donors and assessed their reactivity. ALP/OXP-specific T cells reacted immediately to the addition of the drugs and bypassed intracellular Ag processing, which is consistent with the "pharmacological interaction with immune receptors" (p-i) concept. This direct activation occurred regardless of HLA-B*58:01 status. Although most OXP-specific T cells from HLA-B*58:01(+) donors were restricted by the HLA-B*58:01 molecule for drug recognition, ALP-specific T cells also were restricted to other MHC class I molecules. This can be explained by in silico docking data that suggest that OXP binds to the peptide-binding groove of HLA-B*58:01 with higher affinity. The ensuing T cell responses elicited by ALP or OXP were not limited to particular TCR Vβ repertoires. We conclude that the drug-specific T cells are activated by OXP bound to HLA-B*58:01 through the p-i mechanism.

Predicting 5-fluorouracil toxicity: DPD genotype and 5,6-dihydrouracil:uracil ratio

AIM Decreased DPD activity is a major cause of 5-fluorouracil (5-FU) toxicity, but known reduced-function variants in the DPD gene (DPYD) explain only a part of DPD-related 5-FU toxicities. Here, we evaluated the baseline (pretherapeutic) plasma 5,6-dihydrouracil:uracil (UH2:U) ratio as a marker of DPD activity in the context of DPYD genotypes. MATERIALS & METHODS DPYD variants were genotyped and plasma U, UH2 and 5-FU concentrations were determined by liquid chromatography-tandem mass spectrometry in 320 healthy blood donors and 28 cancer patients receiving 5-FU-based chemotherapy. RESULTS Baseline UH2:U ratios were strongly correlated with generally low and highly variable U concentrations. Reduced-function DPYD variants were only weakly associated with lower baseline UH2:U ratios. However, the interindividual variability in the UH2:U ratio was reduced and a stronger correlation between ratios and 5-FU exposure was observed in cancer patients during 5-FU administration. CONCLUSION These results suggest that the baseline UH2:U plasma ratio in most individuals reflects the nonsaturated state of DPD and is not predictive of decreased DPD activity. It may, however, be highly predictive at increased substrate concentrations, as observed during 5-FU administration.

The impact of a register on the management of neonatal cooling in Switzerland.

BACKGROUND Therapeutic hypothermia following hypoxic ischaemic encephalopathy in term infants was introduced into Switzerland in 2005. Initial documentation of perinatal and resuscitation details was poor and neuromonitoring insufficient. In 2011, a National Asphyxia and Cooling Register was introduced. AIMS To compare management of cooled infants before and after introduction of the register concerning documentation, neuromonitoring, cooling methods and evaluation of temperature variability between cooling methods. STUDY DESIGN Data of cooled infants before the register was in place (first time period: 2005-2010) and afterwards (second time period: 2011-2012) was collected with a case report form. RESULTS 150 infants were cooled during the first time period and 97 during the second time period. Most infants were cooled passively or passively with gel packs during both time periods (82% in 2005-2010 vs 70% in 2011-2012), however more infants were cooled actively during the second time period (18% versus 30%). Overall there was a significant reduction in temperature variability (p < 0.001) comparing the two time periods. A significantly higher proportion of temperature measurements within target temperature range (72% versus 77%, p < 0.001), fewer temperature measurements above (24% versus 7%, p < 0.001) and more temperatures below target range (4% versus 16%, p < 0.001) were recorded during the second time period. Neuromonitoring improved after introduction of the cooling register. CONCLUSION Management of infants with HIE improved since introducing the register. Temperature variability was reduced, more temperature measurements in the target range and fewer temperature measurements above target range were observed. Neuromonitoring has improved, however imaging should be performed more often.