Analysis of Transfusion-Related Acute Lung Injury and Possible Transfusion-Related Acute Lung Injury Reported to the French Hemovigilance Network From 2007 to 2013.

Using the French Hemovigilance Network database from 2007 to 2013, we provide information on demographics, incidence, and risk factors of reported transfusion-related acute lung injury (TRALI) and possible TRALI, analyze TRALI mitigation efforts for fresh frozen plasma and platelet concentrates, and consider the impact of platelet additive solutions on TRALI incidence. We applied the Toronto consensus conference definitions for TRALI and possible TRALI. Two TRALI subgroups were considered: "antibody positive" when a donor has human leukocyte antigen (class I or II) and/or human neutrophil antigen antibodies and the recipient has cognate antigen, and "antibody negative" when immunological investigation is negative or not done. The analysis targeted 378 cases, divided into antibody-positive TRALI (n=75), antibody-negative TRALI (n=100), and possible TRALI (n=203). TRALI patients were younger and received more blood components than the general population of transfused patients. Moreover, we identified the following clinical conditions where patients seemed to be at higher risk to develop TRALI: postpartum hemorrhage, acute myeloid leukemia, liver transplantation, allogeneic and autologous hematopoietic stem cells transplantation, polytrauma, and thrombotic microangiopathy. Policy measures intended to reduce antibody-positive TRALI were found effective for apheresis platelet concentrates and fresh frozen plasma but not for whole blood-derived platelet concentrates. The use of platelet additive solutions was associated with a significant reduction in the incidence of TRALI following transfusion of buffy coat-derived platelet concentrates but not following transfusion of apheresis platelets. Our data reinforce the concept that possible TRALI and TRALI, as defined in the Canadian consensus conference, share many characteristics. No specific policy measures are currently directed at mitigation of possible TRALI despite its impact on transfusion safety. Despite TRALI mitigation measures, the overall incidence of TRALI cases reported to the French Hemovigilance system was not significantly reduced. Therefore, additional research is needed to reduce, if not eradicate, all TRALI categories.

[Immunological safety of transfusion]. / Sécurité immunologique des transfusions.

Transfusion safety lies on the strict application of measures aimed: at avoiding the occurrence of acute hazards, as far as they can be prevented by e.g. the ABO compatibility for red blood cell concentrates and therapeutic plasma; at reducing the frequency of other acute accidents such as TRALI or post-transfusion GVH (based on the implementation of measures which prove to be largely efficacious though not completely); and at reducing delayed incidents and hazards. The implementation of such immunological safety measures also aim at favoring the transfusion efficacy, in avoiding the lysis of transfused red cells or platelets. Perfect immunological compatibility (match) is impossible because transfused cells expose several hundreds of molecular variants with antigenic properties. Adaptive immunity is largely based upon antigen/antibody conflicts and it predominates in transfusion immunological hazards, but inflammation (as well as other components of innate immunity) is now acknowledged as a major actor of transfusion immunological linked hazards.

Transfusion-related acute lung injury: reports to the French Hemovigilance Network 2007 through 2008.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a major cause of transfusion-related mortality and morbidity. Epidemiologic studies using data from national transfusion schemes can help achieve a better understanding of TRALI incidence. STUDY DESIGN AND METHODS: A multidisciplinary working group analyzed TRALI cases extracted from the French Hemovigilance Network Database (2007-2008). All notified cases were reviewed for diagnosis. Those meeting the Canadian Consensus Conference criteria for TRALI were classified according to imputability to transfusion and clinical severity. Patient data (clinical characteristics, number and types of products transfused, and serology results) were obtained. RESULTS: There were 62 TRALI cases and 23 possible TRALI cases during the 2-year period. An immune-mediated mechanism was identified in 30 of 50 TRALI cases with complete serology. TRALI was considered to be the cause of death in 7.1% of patients and might have contributed to death in an additional 9.4% of TRALI or possible TRALI patients. Occurrence ranked high in obstetrics (15%), after surgery (34%), and in hematologic malignancies (21%). Single-donor high-plasma-volume components were involved in half of the cases where the implicated blood product could be determined and carried the highest risk per component (1:31,000 for single-donor fresh-frozen plasma units and apheresis platelet [PLT] concentrates, and 1:173,000 for red blood cells). No incident could be definitively related to the transfusion of solvent/detergent-treated pooled plasma (>200,000 units transfused), nor to pooled PLT concentrates. CONCLUSION: The proportion of TRALI cases related to plasma-rich components was lower than previously described.

Fetal alloimmune thrombocytopenia: is less invasive antenatal management safe?

OBJECTIVES: The aim of this study was to review recent multicenter data on antenatal management of anti-HPA-1a fetal alloimmune thrombocytopenia and, based on this retrospective study and on recent literature, to evaluate if FBS modified the obstetrical management. MATERIAL AND METHODS: This retrospective study in France includes 23 pregnancies in 21 women who had a previous thrombocytopenic infant due to anti HPA-1a alloimmunization. All pregnant women received intravenous immunoglobulin (IVIG) treatment, with or without corticosteroids. Fetal blood sampling (FBS) was performed before any therapy (four cases) or during pregnancy (nine cases). RESULTS: Infants whose mother received treatment had a significantly higher neonatal platelet count than the corresponding sibling (p = 0.003). In eight cases, therapy was started late during pregnancy. In three cases, treatment was discontinued 3 or 4 weeks before birth, and this was associated with a poorer result. No in utero intracranial hemorrhage was recorded in the infants for whom maternal therapy continued to term. Adverse effects were not observed in any case. All babies were delivered by cesarean even when FBS was performed. One emergency cesarean was performed for fetal bradycardia after FBS. CONCLUSION: This study confirmed that maternal therapy with intravenous immunoglobulin for fetal alloimmune thrombocytopenia gives satisfactory results. It also showed that a less invasive approach, especially a reduction in the number of fetal blood samples, is possible without deleterious consequences. This observation suggests also to start IVIG early during pregnancy and to continue treatment up to delivery.

Intravenous immunoglobulins for neonatal alloimmune neutropenia refractory to recombinant human granulocyte colony-stimulating factor.

Neonatal alloimmune neutropenia (NAN) results from neutrophil destruction by transplacental maternal neutrophil-specific immunoglobulin G (IgG) antibodies directed against the antigen inherited from the father. Treatment is usually based on recombinant human granulocyte colony-stimulating factor (G-CSF) and prevention or treatment of infection. We report the case of neutropenia in a newborn discovered because of fetomaternal infection. The bone marrow biopsy showed normal cellularity. Granulocyte typing, granulocyte cross-matching, and serum assays showed anti-neutrophil antibodies specific for human neutrophil antigen-1c, an antigen rarely involved in this disease. This NAN was refractory to G-CSF but responded to intravenous immunoglobulin (IVIG). IVIG should be considered as a second-line treatment in NAN refractory to G-CSF. Clinical trials, however, are required to define the optimal management of NAN, a rare but probably underestimated life-threatening situation for newborns.

Granulocyte antibody screening: evaluation of a bead-based assay in comparison with classical methods.

BACKGROUND: Granulocyte antibodies have been implicated in allo- and autoimmune neutropenia and in transfusion reactions. STUDY DESIGN AND METHODS: Fifty-one sera from suspected alloimmune neutropenia or transfusion-related acute lung injury (TRALI) and 40 sera from suspected autoimmune neutropenia were tested for granulocyte antibodies using LABScreen MULTI (One Lambda, Inc.), compared with classical tests (flow cytometry [FC] and granulocyte agglutination [GAT] followed by monoclonal antibody-specific immobilization of granulocyte antigens [MAIGA]). RESULTS: In alloimmune situations, 48 sera were concordant (94%), two sera positive for HNA with LABScreen MULTI were negative by FC/GAT and/or MAIGA, and one serum sample negative for HNA with LABScreen MULTI was positive by classical tests. In autoimmune neutropenia, 30 sera were concordant (75%), four sera positive for HNA with LABScreen MULTI were negative by FC/GAT and/or MAIGA, and six sera negative for HNA with LABScreen MULTI were positive by FC/GAT and/or MAIGA. For detection of autoantibodies, the LABScreen MULTI was less concordant. However, with the exception of one case, the discrepancies were observed in sera that did not show a clear specificity. CONCLUSIONS: LABScreen MULTI correlated well with our classical methods for HNA-1 and HNA-2a antibody screening. It can be used for screening blood donors or patients suspected of TRALI, but GAT is still needed for HNA-3a antibody screening.

Evaluation of the tuberculin skin test and the interferon-gamma release assay for TB screening in French healthcare workers.

INTRODUCTION: Using French cut-offs for the Tuberculin Skin Test (TST), results of the TST were compared with the results of an Interferon-gamma Release Assay (IGRA) in Healthcare Workers (HCW) after contact to AFB-positive TB patients. METHODS: Between May 2006 and May 2007, a total of 148 HCWs of the University Hospital in Nantes, France were tested simultaneously with IGRA und TST. A TST was considered to indicate recent latent TB infection (LTBI) if an increase of >10 mm or if TST >/= 15 mm for those with no previous TST result was observed. For those with a positive TST, chest X-ray was performed and preventive chemotherapy was offered. RESULTS: All HCWs were BCG-vaccinated. The IGRA was positive in 18.9% and TST >/= 10 mm was observed in 65.5%. A recent LTBI was believed to be highly probable in 30.4% following TST. Agreement between IGRA and TST was low (kappa 0.041). In 10 (16.7%) out of 60 HCWs who needed chest X-ray following TST the IGRA was positive. In 9 (20%) out of 45 HCWs to whom preventive chemotherapy was offered following TST the IGRA was positive. Of those considered TST-negative following the French guidelines, 20.5% were IGRA-positive. In a two-step strategy - positive TST verified by IGRA - 18 out of 28 (64.3%) IGRA-positive HCWs would not have been detected using French guidelines for TST interpretation. CONCLUSION: The introduction of IGRA in contact tracings of BCG-vaccinated HCWs reduces X-rays and preventive chemotherapies. Increasing the cut-off for a positive TST does not seem to be helpful to overcome the effect of BCG vaccination on TST.

The alloimmune response to the human platelet antigen-1a is not related to maternal-fetal killer immunoglobulinlike receptor/HLA-Cw combinations.

BACKGROUND: Human platelet antigen (HPA)-1a fetomaternal alloimmune thrombocytopenia, responsible in the most severe cases for fetal or neonatal intracranial hemorrhages leading to death or survival with neurologic sequelae, was shown to be restricted to the human leukocyte antigen (HLA) Class II DRB3*0101-encoded molecule. Whereas more than 90 percent of alloimmunized mothers display the DRB3*0101 allele, the positive predictive value of the presence of DRB3*0101 is only 35 percent. Additional genetic risk factors may exist of which elucidation could improve the undertaking of incompatible pregnancies in at-risk families, encouraging an antenatal screening. Interactions of killer immunoglobulinlike receptors (KIRs) on maternal decidual NK cells with HLA-Cw molecules on fetal trophoblasts were reported as one of the mechanisms involved in the fetomaternal tolerance during pregnancy. STUDY DESIGN AND METHODS: Genotyping was performed of 16 KIR genes in HPA-1a-negative/DRB3*0101-positive alloimmunized mothers and in HPA-1a-negative/DRB3*0101-positive nonimmunized mothers as well as HLA-Cw genotyping in thrombocytopenic children and their nonaffected siblings. RESULTS: No particular KIR genes or KIR genotypes were observed in the alloimmunized or nonimmunized mothers. Distribution of HLA-Cw genes in affected infants and nonaffected siblings did not reveal any HLA-Cw specificity associated with triggering or modulation of the HPA-1a alloimmunization. No maternal KIR/fetal HLA-Cw combinations were demonstrated in association with a detrimental or a protective effect on the HPA-1a alloimmunization. CONCLUSION: Maternal KIR/fetal HLA-Cw gene combinations that are involved in the fetomaternal tolerance do not appear to play a role in the HPA-1a alloimmunization.

Transfusion related acute lung injury (TRALI) caused by red blood cell transfusion involving residual plasma anti-HLA antibodies: a report on two cases and general considerations.

TRALI is considered a serious hazard among immune complications of blood transfusion and its occurrence is admitted to be globally underestimated. Each type of blood product is likely to cause TRALI. We report here on two consecutive observations of TRALI caused by red blood cell concentrates, in which anti-HLA class I and class II antibodies resulting from post-gravitational allo-immunization were evidenced in donors. HLA class I and II antigenic community between recipients and donors' husbands were found and strong reacting IgG antibodies directed at several of those common antigens were detected in the donors' serum. Both donors had more than 3 pregnancies, raising the issue of blood donor selection or of plasma reduction for cellular products.

Comparison of different kits in the detection of autoantibodies to cardiolipin and beta2glycoprotein 1.

OBJECTIVE: To estimate the performance characteristics of 10 commercial kits and one in-house kit for the detection and quantification of anticardiolipin (aCL) (six kits) and anti-beta2glycoprotein 1 (anti-beta2GP1) (five kits) antibodies, and to evaluate the degree of variability between these different kits. METHODS: We determined the presence of aCL and anti-beta2GP1 IgG and IgM antibodies in 67 sera from 62 patients and reviewed the data separately. Each serum sample was tested with six commercial aCL determination kits and with four commercial and one in-house anti-beta2GP1 determination kit. We then analysed the operating characteristics of each kit (sensitivity, specificity, positive and negative predictive values) and we analysed the absolute and 2 x 2 agreements. RESULTS: The 62 patients included had primary antiphospholipid syndrome (APS) in 10 cases, secondary APS for eight, systemic lupus (SLE) for 23 and other diagnoses for the remaining 21. Operating characteristics differed from one kit to another. Good agreement was found using sensitive aCL determination kit and specific anti-beta2GP1 determination kit. Agreement between kits was medium for IgG aCL. 2 x 2 concordance studies showed a group of three aCL kits which were quite homogenous and showed that all anti-beta2GP1 kits formed quite a homogenous group. CONCLUSION: A high degree of variability still persists for aCL antibody determination posing the question of the qualification of commercial or in-house kits and the question of standardization of results. A better concordance is found for high positive results. Good agreement exists for anti-beta2GP1 kits. aCL determination is still needed and should be complemented by anti-beta2GP1 determination.

Rats injected with syngenic rat apoptotic neutrophils develop antineutrophil cytoplasmic antibodies.

Antineutrophil cytoplasmic antibodies (ANCA) are present in sera from patients with various forms of vasculitis-associated glomerulonephritis. Because autoantibodies may be directed against antigens presented by apoptotic cells, generation of ANCA using apoptotic neutrophils (PMN) in syngenic Brown Norway (BN) rats was attempted. These rats are T-helper type 2-prone animals, already used successfully in other ANCA-positive animal models. BN rats received repeated injections of buffer or of nonapoptotic or apoptotic PMN aged in cultures, in the footpad and once intravenously. Four of five rats that received injections of PMN aged for 48 h developed ANCA, which cross-reacted with human leukocyte elastase in three cases. None of the rats that received injections of freshly isolated neutrophils developed ANCA. One rat that received buffer injection and that exhibited chronic skin infection developed delayed ANCA. None of the rats showed signs of disease: no weight loss and no proteinuria. Then a subnephritogenic dose of antibody directed against rat glomerular basement membrane was injected. Rats then were killed, and different organs were frozen and studied. No significant lesions were found in kidneys or lungs. It is concluded that injections of apoptotic but not freshly isolated PMN can generate ANCA in BN rats. Additional studies are needed to elucidate the immunization mechanism and the ability of these autoantibodies to initiate vasculitis in these experimental animals.