Reduction of anti-K-mediated hemolytic disease of newborns after the introduction of a matched transfusion policy: a nation-wide policy change evaluation study in the Netherlands

Background: During pregnancy, maternal red blood cell (RBC) antibodies can lead to life-threatening fetal hemolysis and anemia. Women can become immunized by a pregnancy or an unmatched transfusion. Our aim was to quantify the effect of a nationwide K-matched transfusion policy for women of childbearing age potential to prevent K-immunization in pregnancy.Study Design and Methods: In this nation-wide policy change evaluation study we determined the occurrence of RBC antibodies before and after introduction of a K-matched transfusion policy and evaluated the cause K alloimmunization 10 years after introduction of this measure. K-matched transfusion for females under 45 years of age is advised in the Dutch transfusion guideline since 2004. We used laboratory data from pregnancies with RBC antibodies identified in the period 1999-2018 obtained as part of a population-based screening program in the Netherlands.Results: Tests of 36 286 pregnancies produced a positive antibody screening result which concerned anti-K in 1550 pregnancies. The occurrence of anti-K decreased from 67.9 to 20.2 per 100 000 pregnancies. The relative risk reduction was 0.70 which largely exceeded the relative risk reduction of 0.27 for antibodies against RBC antigens for which no preventive matching is required. The number of pregnancies at risk for anti-K-mediated disease decreased from 9.7 to 4.2 per 100 000 pregnancies.Conclusions: A K-matched transfusion policy is associated with a major decrease in a number of pregnant women with anti-K and pregnancies at risk for anti-K-mediated disease. A relatively simple measure is now shown to impact prevention of hemolytic disease in the fetus and newborn.Clinical epidemiolog

Aspects of Innate and Adaptive Immune responses during Respiratory Syncytial Virus Infection

Respiratory Syncytial Virus (RSV) infections are a major cause of lower respiratory tract disease and represent a major disease burden in infants, immune compromised patients and the elderly. Despite the identification and isolation of the virus in 1956, extensive efforts since then to develop a safe vaccine or effective antiviral therapy are without clear success. A vaccine trial in the 1960s caused enhanced disease when vaccines were exposed to the natural virus. The only approved intervention is the use of a prophylactic monoclonal antibody which is applied in high risk infants. Adaptive memory responses elicited during natural infections with RSV do not provide complete protection. The exact mechanism behind severe primary disease in humans is still poorly understood, and the mechanism behind vaccine enhanced respiratory disease while studied extensively in mouse models have not lead to clear insights for better vaccine approaches. Thorough knowledge of the complex interactions between the virus and the host immune system might eventually bring to light alternative strategies to protect against severe RSV infections, but this remains a great challenge. In the past 50 years, since its initial discovery, many studies have been performed that have shed light on epidemiology, disease, immunity and vaccine development in relation to RSV. Major questions that remain are; (I) why do certain otherwise healthy children develop severe RSV lower respiratory tract infection, while the majority of the birth cohort presents with a mild disease? (II) Why is immunity to RSV incomplete and are healthy persons frequently re-infected? (III) How to protect those at risk for severe RSV disease, is vaccination for RSV desirable at young age or are there alternative methods more suitable and effective? In this thesis we try to shed light on certain aspects of these questions by studying the involvement of different cell types and their pathogen recognition receptors in the induction of RSV specific responses in mouse models and the kinetics of primary immune response in children with severe RSV infections. In conclusion, although the exact mechanism of severe RSV disease in humans is still unclear, the sequence of events during severe primary RSV infection in infants indicates that T cells are probably not directly contributing to disease severity. The lack of a clear correlation between viral load and disease indicates that modulation of innate immunity during infection should be considered an alternative strategy to reduce illness. Furthermore, humans are capable of generating highly neutralizing antibodies that can limit viral load, but not completely protect against frequent re-infections indicating complex interactions between RSV and protective innate and T cell responses. Caution should be taken in directly translating data obtained from murine studies to the human system as different parameters of the infection are responsible for disease

Characterization of the CD8+ T cell responses directed against respiratory syncytial virus during primary and secondary infection in C57BL/6 mice.

The BALB/c mouse model for human respiratory syncytial virus infection has contributed significantly to our understanding of the relative role for CD4+ and CD8+ T cells to immune protection and pathogenic immune responses. To enable comparison of RSV-specific T cell responses in different mouse strains and allow dissection of immune mechanisms by using transgenic and knockout mice that are mostly available on a C57BL/ 6 background, we characterized the specificity, level and functional capabilities of CD8+ T cells during primary and secondary responses in lung parenchyma, airways and spleens of C57BL/6 mice. During the primary response, epitopes were recognized originating from the matrix, fusion, nucleo- and attachment proteins, whereas the secondary response focused predominantly on the matrix epitope. C57BL/6 mice are less permissive for hRSV infection than BALB/c mice, yet we found CD8+ T cell responses in the lungs and bronchoalveolar lavage, comparable to the responses described for BALB/c mice. © 2006 Elsevier Inc. All rights reserved. Keywords: Respiratory syncytial virus; C57BL/6; CD8+ T cells; Inactivation; Tetrame

Dynamics of human respiratory virus-specific CD8+ T cell responses in blood and airways during episodes of common cold.

Contains fulltext : 70459.pdf (publisher's version ) (Closed access)We determined the dynamics of CD8(+) T cells specific for influenza virus and respiratory syncytial virus in blood and tracheostoma aspirates of children during the course of respiratory infections. We showed that during localized respiratory infections the ratio of activated effector CD8(+) T cells to resting memory/naive CD8(+) T cells in peripheral blood increased significantly. Furthermore, the number of effector/memory T cells specific for respiratory viruses declined in blood and increased in the airways, suggesting that these T cells redistributed from blood to airways. T cells specific for the infecting virus were present in the airways for longer periods at increased levels than nonspecifically recruited bystander T cells. After clearance of the infection, the ratio of resting memory and naive CD8(+) T cells normalized in peripheral blood and also memory T cell numbers specific for unrelated viruses that declined during the infection due to bystander recruitment were restored. Taken together, these results showed a significant systemic T cell response during relatively mild secondary infections and extensive dynamics of virus-specific and nonspecific Ag-experienced T cells

CD8+ T cell responses in bronchoalveolar lavage fluid and peripheral blood mononuclear cells of infants with severe primary respiratory syncytial virus infections.

Contains fulltext : 52901.pdf (publisher's version ) (Closed access)A protective role for CD8+ T cells during viral infections is generally accepted, but little is known about how CD8+ T cell responses develop during primary infections in infants, their efficacy, and how memory is established after viral clearance. We studied CD8+ T cell responses in bronchoalveolar lavage (BAL) samples and blood of infants with a severe primary respiratory syncytial virus (RSV) infection. RSV-specific CD8+ T cells with an activated effector cell phenotype: CD27+CD28+CD45RO+CCR7-CD38+HLA-DR+Granzyme B+CD127- could be identified in BAL and blood. A high proportion of these CD8+ T cells proliferated and functionally responded upon in vitro stimulation with RSV Ag. Thus, despite the very young age of the patients, a robust systemic virus-specific CD8+ T cell response was elicited against a localized respiratory infection. RSV-specific T cell numbers as well as the total number of activated effector type CD8+ T cells peaked in blood around day 9-12 after the onset of primary symptoms, i.e., at the time of recovery. The lack of a correlation between RSV-specific T cell numbers and parameters of disease severity make a prominent role in immune pathology unlikely, in contrast the T cells might be involved in the recovery process