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This paper reports clinical, haematological, virological, serological, pathological, and toxicological findings in young calves suffering from an apparently novel disease that is characterized by haemorrhagic diathesis on the basis of severe bone marrow damage and is almost always fatal. No evidence for infection with BVDV or BTV or for intoxicatio...
Contexts in source publication
Context 1
... 2008 and, these cows were also vaccinated against Blueton- gue (Bluevac-8 ® : Boehringer/CZV Veterinaria). Informa- tion on these four dams is given in Table 1 ...
Context 2
... calves born within a 30 hour interval (July 2009) were purchased from two large dairy farms (I and II) where BNP has never occurred previously (and has not occurred since). The calves (see Table 1) were delivered by three (9, 6, and 4 year-old) Holstein Friesian (HF) and two (10 and 3 year-old) Brown Swiss cows. Calves 5 and 6 were mixed twins born by an HF cow. ...
Context 3
... not all colostrum samples exceeded three litres, some calves received a mixture of colostrum batches from two different cows. The matching of experimental calves and colostrum batches is listed in Table 1. The first colostrum intake was between 1.5 and 4.5 hours after birth and all calves, except the twins (no. 5 and 6) received the colostrum on their farm of origin. ...
Context 4
... control calves received three litres colostrum each from their own dams, which was milked at the clinic and offered to the calves within 1 to 3 hours after birth (Table 1). ...
Context 5
... aetiological role of colostrum seems to be con- firmed by the results of this study. The data presented in Table 1 indicate that all batches of colostrum used had the potential to cause BNP. The colostrum donor cows were selected specifically because they had already had at least one calf affected by BNP. ...
Citations
... Affected calves were mostly less than four weeks of age, and the clinical signs ranged from fever, petechiae in mucosa, cutaneous haemorrhage, and melaena to extensive bleeding of the skin. Affected calves had been born healthy and no clinical signs were obvious until the second or third week of life [1,[12][13][14][15]. On post-mortem examination, calves showed generalised haemorrhages and an anaemic appearance. ...
Background:
Bovine neonatal pancytopenia (BNP) is a haemorrhagic disease of neonatal calves. BNP was first described in Germany in 2009, later on also in other European countries, and in New Zealand in 2011. The disease is characterised by spontaneous bleeding, pancytopaenia in the bone marrow, and a high case fatality ratio. The causal role of a specific bovine viral diarrhoea virus (BVDV) vaccine (PregSure®BVD, then Pfizer Animal Health, now Zoetis, Berlin, Germany) has been established over the last years, causing the production of alloantibodies in some vaccinated cattle, which in the case of pregnant cattle, are transferred to the newborn calf via the colostrum. However, striking regional differences in the incidence of the disease were observed within Germany and other countries, but as the disease was not notifiable, no representative data on the spatial distribution are available. In this study, we address the spatial distribution and incidence of BNP using the results of two representative surveys amongst cattle practitioners in Bavaria, Germany. The surveys, asking about the occurrence of BNP, were conducted in 2009 and 2010. Answers were analysed spatially by testing for clusters using space-time models. Practitioners were also asked how many cows they serve in their practice and this number was used to estimate the incidence of BNP. Furthermore, in the survey of 2010, practitioners were also asked about usage of vaccine against BVDV.
Results:
From the results of the surveys, three clusters were identified in Bavaria. These clusters also coincided with the usage of the specific BVDV vaccine as indicated by the veterinary practices. Furthermore, the representative surveys allow the estimation of the incidence of BNP to be in the order of 4 cases per 10,000 calves at risk.
Conclusions:
The study is the only representative survey conducted on BNP. Despite the fact that BNP is a non-infectious disease, regional clusters were identified.
... inTrODUcTiOn Bovine neonatal pancytopenia (BNP) was a hemorrhagic disease in young cattle that emerged in most EU states in 2007 (1)(2)(3)(4)(5) and later in New Zealand (6). The condition was characterized by an increased susceptibility to bleeding from various body parts in young calves and a high-mortality rate. ...
... The condition was characterized by an increased susceptibility to bleeding from various body parts in young calves and a high-mortality rate. The cause of internal and/ or external bleeding was a widespread and severe destruction of the bone marrow, resulting in depletion of hematopoietic stem cells leading to thrombocytopenia, non-regenerative anemia, and leukopenia (3,7). Epidemiological data and experimental studies revealed that the dams that gave birth to calves affected by BNP were immunized with PregSure ® BVD, a highly adjuvanted vaccine against bovine viral diarrhea (BVD) (4,8). ...
Bovine neonatal pancytopenia (BNP) was a vaccine-induced alloimmune disease observed in young calves and characterized by hemorrhages, pancytopenia, and severe destruction of the hematopoietic tissues. BNP was induced by alloreactive maternal antibodies present in the colostrum of certain cows vaccinated with a highly adjuvanted vaccine against bovine viral diarrhea. Bioprocess impurities, originating from the production cell line of the vaccine, are likely to have induced these alloreactive antibodies. One prominent alloantigen recognized by vaccine-induced alloantibodies is highly polymorphic bovine major histocompatibility complex class I antigen (bovine leukocyte antigen 1-BoLA I). Aim of this study was to define the fine specificity of BNP-associated anti-BoLA I alloantibodies. In total, eight different BoLA I alleles from the production cell line were identified. All genes were cloned and recombinantly expressed in murine cell lines. Using these cells in a flow cytometric assay, the presence of BoLA I specific alloantibodies in BNP dam sera was proven. Three BoLA I variants were identified that accounted for the majority of vaccine-induced BoLA I reactivity. By comparing the sequence of immunogenic to non-immunogenic BoLA I variants probable minimal epitopes on BoLA I were identified. In general, dams of BNP calves displayed high levels of BoLA I reactive alloantibodies, while vaccinated cows delivering healthy calves had significantly lower alloantibody titers. We identified a subgroup of vaccinated cows with healthy calves displaying very high alloantibody titers. Between these cows and BNP dams no principle difference in the BoLA I reactivity pattern was observed. However, with a limited set of dam-calf pairs it could be demonstrated that serum from these cows did not bind to BoLA I expressing leukocytes of their offspring. By contrast, when testing cells from surviving BNP calves with the corresponding dam's serum there was significant binding. We therefore conclude that predominantly highly alloreactive cows are at risk to induce BNP and it depends on the paternally inherited BoLA I whether or not the calf develops BNP. © 2018 Kasonta, Mauritz, Spohr, Sauter-Louis, Duchow, Cussler, Holsteg and Bastian.
... BNP was a disease of newborn calves with an extremely high lethality rate of 90% (8). Since 2006, BNP first occurred in southern Germany (9) and then in several other countries (10). ...
A BVD vaccine with novel production technology and adjuvant was introduced to improve immune responses against BVD. However, 5-10% of vaccinated cattle produced pathogenic antibodies, which transferred bovine neonatal pancytopenia (BNP) via colostrum to almost any calf given respective colostrum. Diseased calves had a very high lethality rate of 90%. Dysregulated immune response of dams to the novel vaccine is not fully understood to date. In this study, we clarified by in-depth characterization of immune capacities if the immune response was changed by this particular vaccine or if these cows were prone to a different type of immune response per se.
There was a marked difference in the response after polyclonal in vitro stimulation of peripheral blood derived lymphocytes (PBL). BNP dams showed a highly significant hyperproliferation to Pokeweed Mitogen (PWM), Concanavalin A (ConA), Musa paradisiaca banana lectin (BanLec) and interleukin-2 (IL-2). Subsequent differential proteome analyses revealed substantial qualitative differences in immune capacities between both cow groups. PBL of BNP dams reacted with a STAT3 regulated response compared to PBL of controls, which used STAT1 pathway after ConA stimulation. We could detect this immune response pattern also in cows that were never vaccinated at all. Therefore, our data prove that respective BVD vaccination did not cause this deviant immune response, but that a deviant immune phenotype (ID) already existed in cattle and still exists. PBL of these ID cows prefer the IL-2/JAK2/STAT3 pathway for immune responses. Since ID cows additionally have a two-fold increased mastitis incidence, our findings have clinical relevance.
... The occurrence of bovine neonatal pancytopenia (BNP) in some European countries in 2007 (Friedrich et al., 2009) led to a sudden surge of cases of bovine HD. High mortality rates and initial uncertainty about the aetiology of BNP resulted in numerous investigations (Bridger et al., 2011;Deutskens et al., 2011;Foucras et al., 2011;Pardon et al., 2011;Kasonta et al., 2012;Lambton et al., 2012;Sauter-Louis et al., 2012;Jones et al., 2013;Benedictus et al., 2014;Bell et al., 2015). ...
Haemorrhagic diathesis (HD) in cattle is a relatively rare syndrome that can have many different causes. With the occurrence of bovine neonatal pancytopenia (BNP) in 2007, the number of cases of HD in cattle has increased. This led to an enhanced interest in diseases presenting with bleeding disorders. The possible causes of HD in cattle, the clinical findings, and the course of various diseases are described and evaluated. Furthermore, we determined whether cases of BNP occurred before the introduction of the vaccine Pregsure BVD since its widespread use was associated with the syndrome. Records of 215 cases of HD in cattle that had been referred to the Clinic for Ruminants with Ambulatory and Herd Health Services at the Centre for Clinical Veterinary Medicine, Ludwig Maximilian University, Munich, between 1982 and 2014 were evaluated. The two most commonly diagnosed diseases were BNP (n = 95) and septicaemia (n = 35), with fatality rates of 82% and 66%, respectively. In 27 (13%) cases, no clear cause for the HD could be designated. Statistically significant differences were found with regard to the course of the various disorders and the clinical findings. A receiver operating characteristic analysis of thrombocyte counts of affected animals at the time of arrival at the clinic did not provide any predictive information on disease outcome. Two cases of HD occurred before the introduction of Pregsure BVD (1989, 1991). In both cases, clinical, haematological, and pathological findings were identical to BNP. The cause of HD in these two cases could not be determined retrospectively.
... Since 2007 an increase in newborn calves with the bleeding syndrome Bovine Neonatal Pancytopenia (BNP) was observed all over Europe123. Epidemiological studies showed a strong association between the occurrence of BNP in calves and vaccination of their dams with the PregSure© BVD vaccine (Pfizer Animal Health) [2] . Symptoms of BNP are severe internal and external bleeding, first seen around 10–20 days of age. ...
Bovine Neonatal Pancytopenia (BNP), a bleeding syndrome of neonatal calves, is caused by alloantibodies absorbed from the colostrum of particular cows. A commercial BVD vaccine is the likely source of alloantigens eliciting BNP associated alloantibodies. We hypothesized that the rare occurrence of BNP in calves born to vaccinated dams could be associated with genetic differences within dams and calves. We found that the development of BNP within calves was a heritable trait for dams, not for calves and had a high heritability of 19%. To elucidate which genes play a role in the development of BNP we sequenced candidate genes and characterized BNP alloantibodies. Alloantigens present in the vaccine have to be presented to the dam’s immune system via MHC class II, however sequencing of DRB3 showed no differences in MHC class II haplotype between BNP and non-BNP dams. MHC class I, a highly polymorphic alloantigen, is an important target of BNP alloantibodies. Using a novel sequence based MHC class I typing method, we found no association of BNP with MHC class I haplotype distribution in dams or calves. Alloantibodies were detected in both vaccinated BNP and non-BNP dams and we found no differences in alloantibody characteristics between these groups, but alloantibody levels were significantly higher in BNP dams. We concluded that the development of BNP in calves is a heritable trait of the dam rather than the calf and genetic differences between BNP and non-BNP dams are likely due to genes controlling the quantitative alloantibody response following vaccination.
Electronic supplementary material
The online version of this article (doi:10.1186/s13567-014-0129-0) contains supplementary material, which is available to authorized users.
... The syndrome affects newborn calves and is characterized by a complete destruction of the red bone marrow, pancytopenia, severe bleeding and high lethality. The syndrome is triggered by ingestion of colostrum from dams that have previously been vaccinated with PregSureBVD, a strongly adjuvanted, inactivated vaccine against bovine viral diarrhea virus (BVDV) [8,9]. Due to its particular composition that combines substantial amounts of bioprocess impurities with a very efficient adjuvant system, this vaccine induces high titres of bovine MHC-I-specific alloantibodies [10][11][12]. ...
In 2006, a new haemorrhagic syndrome affecting newborn calves, Bovine Neonatal Pancytopenia (BNP), was reported in southern Germany. It is characterized by severe bleeding, destruction of the red bone marrow, and a high case fatality rate. The syndrome is caused by alloreactive, maternal antibodies that are ingested by the calf with colostrum and result from a dam vaccination with one particular vaccine against Bovine-Viral-Diarrhoea-Virus. Because bovine colostrum is increasingly gaining interest as a dietary supplement for human consumption, the current study was initiated to elucidate whether BNP alloantibodies from BNP dams (i.e. animals that gave birth to a BNP-affected calf) cross-react with human cells, which could pose a health hazard for human consumers of colostral products. The present study clearly demonstrates that BNP alloantibodies cross-react with human lymphocytes in vitro. In agreement with previous reports on BNP, the cross-reactive antibodies are specific for MHC-I molecules, and sensitize opsonised human cells for in vitro complement lysis. Cross-reactive antibodies are present in serum and colostrum of individual BNP dams. They can be traced in commercial colostrum powder manufactured from cows immunized with the vaccine associated with BNP, but are absent from commercial powder manufactured from colostrum excluding such vaccinated cows. In humans alloreactive, MHC-I specific antibodies are generally not believed to cause severe symptoms. However, to minimize any theoretical risk for human consumers, manufacturers of bovine colostrum for human consumption should consider using only colostrum from animals that have not been exposed to the vaccine associated with BNP.
... However, application of vaccination regimes requires a comprehensive knowledge about all potential vaccination effects. Bovine neonatal pancytopenia (BNP) is a new disease of new-born calves characterised by extreme haemorrhages, thrombocytopenia, leukocytopenia, and cellular depletion of the bone marrow [2]. BNP ends lethally in the vast majority of cases, and no specific treatment is available. ...
Bovine neonatal pancytopenia (BNP) is a new fatal, alloimmune/alloantibody mediated disease of new-born calves induced by ingestion of colostrum from cows, which had been vaccinated with a specific vaccine against the Bovine Virus Diarrhoea Virus (BVDV). The hypothesis of pathogenic MHC class I molecules in the vaccine had been put up, but no formal proof of specific causal MHC class I alleles has been provided yet. However, the unique features of the vaccine obviously result in extremely high specific antibody titres in the vaccinated animals, but apparently also in further molecules inducing BNP. Thus, a comprehensive picture of the immune response to the vaccine is essential. Applying the novel approach of next generation RNA sequencing (RNAseq), our study provides a new holistic, comprehensive analysis of the blood transcriptome regulation after vaccination with the specific BVDV vaccine. Our RNAseq approach identified a novel cytokine-like gene in the bovine genome that is highly upregulated after vaccination. This gene has never been described before in any other species and might be specific to ruminant immune response. Furthermore, our data revealed a very coordinated immune response to double-stranded (ds) RNA or a dsRNA analogue after vaccination with the inactivated single-stranded (ss) RNA vaccine. This would suggest either a substantial contamination of the vaccine with dsRNA from host cells after virus culture or a dsRNA analogue applied to the vaccine. The first option would highlight the potential risks associated with virus culture on homologous cells during vaccine production; the latter option would emphasise the potential risks associated with immune stimulating adjuvants used in vaccine production.
... First seen in 2007 (Friedrich et al., 2009 ), bovine neonatal pancytopenia (BNP) affects neonatal calves under four weeks of age from different breeds and gender. It is characterized by high susceptibility to internal or external bleeding due to severe pancytopenia and bone marrow depletion leading to a high mortality rate (Friedrich et al., 2009; Kappe et al., 2010; Pardon et al., 2009). ...
... First seen in 2007 (Friedrich et al., 2009 ), bovine neonatal pancytopenia (BNP) affects neonatal calves under four weeks of age from different breeds and gender. It is characterized by high susceptibility to internal or external bleeding due to severe pancytopenia and bone marrow depletion leading to a high mortality rate (Friedrich et al., 2009; Kappe et al., 2010; Pardon et al., 2009). In the initial phase, haematology shows leukocytopenia and thrombocytopenia (Friedrich et al., 2009; Pardon et al., 2009). ...
... It is characterized by high susceptibility to internal or external bleeding due to severe pancytopenia and bone marrow depletion leading to a high mortality rate (Friedrich et al., 2009; Kappe et al., 2010; Pardon et al., 2009). In the initial phase, haematology shows leukocytopenia and thrombocytopenia (Friedrich et al., 2009; Pardon et al., 2009). Although infection with bovine viral diarrhoea virus (BVDV) can cause similar clinical symptoms, no BVD viral antigen was isolated in affected calves (Bell et al., 2010). ...
Bovine neonatal pancytopenia (BNP) is mainly characterized by multiple haemorrhages, thrombocytopenia and leukocytopenia as a result of bone marrow depletion. BNP can be induced in healthy calves through application of colostrum from BNP donors, proofing that BNP is mediated to maternal alloantibodies. Alloantibody binding to bovine blood cells is present in sera and colostra of BNP donors and is probably initialized by vaccination with a certain BVD vaccine. To understand etiology and pathomechanisms of BNP, we closely characterized disease inducing antibodies regarding immunoglobulin subclass and binding specificities to peripheral blood derived leukocytes and platelets. By exact phenotyping the targeted blood cell subsets, including platelets for the first time, we investigated that BNP alloantibodies are exclusively of IgG1 subclass. Interestingly, IgG1 of BNP colostra bound to 70% leukocytes and 100% platelets irrespective of different bovine breeds and cellular maturity of all specimens tested. Furthermore, staining pattern on platelets as well as leukocyte subsets by BNP-IgG1 alloantibody exposed 100% reactivity to platelets, granulocytes and monocytes. Interestingly, the main part of T-helper cells was not bound by colostral alloantibodies. Our results point to a crucial role of IgG1 antibodies in BNP and to a target antigen that is expressed by all cells of myeloid lineage, but only partially by the lymphoid lineage.
... The principal clinical signs of mucosal petechiae, bleeding after injections, various amounts of blood in the faeces, spontaneous cutaneous haemorrhages, and severe secondary infections can be explained by the pronounced thrombocytopenia and leukocytopenia Brugère-Picoux, 2009;Corbière et al., 2009;Doll et al., 2009;Friedrich et al., 2008Friedrich et al., , 2009aGentile et al., 2009;Kappe et al., 2010;Pardon et al., 2009Pardon et al., , 2010Penny et al., 2009;Sanchez-Miguel et al., 2010;Smolenaars and Mars, 2009). In affected calves bone marrow is profoundly affected with reduction of megakaryocytes, lymphoid and myeloid precursor cells (panmyelophthisis) (Friedrich et al., 2009b;Pardon et al., 2010;Kappe et al., 2010). ...
... Calves of both genders were similarly affected and the disease was observed in several breeds, such as Simmental, Holstein Friesians, Brown Swiss, Belgian Blue, Charolais, Blonde d'Aquitaine, Limousin, Aberdeen Angus, Montbéliard, as well as in various cross breeds. There were no obvious irregularities in the relative frequency of the breed distribution Corbière et al., 2009;Doll et al., 2009;Friedrich et al., 2009b;Gentile et al., 2009;Kappe et al., 2010;Pardon et al., 2010;Penny et al., 2009;Smolenaars and Mars, 2009). Data available to the different research groups on the frequency of occurrence of BNP are probably incomplete because BNP is not notifiable in any country and the disease may be overlooked because it is rare and calves may die without farmers realising that it was BNP. ...
... In the questionnaire it was asked explicitly for contact with these plants, either directly or through hay and silage, but only few farm owners (case farms 3/50; control farms 5/100) mentioned that access to these plants could not be excluded completely. In addition, the intake of these toxic agents would have had to be present for a prolonged period to cause clinical disease, while most calves affected were about 2 weeks of age (Friedrich et al., 2009b). Also, only in few case and control farms access to rodenticides could not be excluded completely for animals. ...
A case control study on farm level was conducted at the Clinic for Ruminants, LMU Munich, to identify possible risk factors associated with the observed increase in numbers of calves showing clinical signs of Bovine Neonatal Pancytopenia (BNP) since 2006 in southern Germany. Interviews were conducted between August 2008 and June 2010. The characteristics of 56 dairy farms with at least one confirmed case of BNP (thrombocytopenia and leukocytopenia and/or typical findings in post-mortem examination and bone marrow histology) were compared with those of two sets of 50 control dairy farms each, with no history of BNP. The first set of 50 control farms was selected randomly from veterinary practices which had never observed a BNP case on the farms they serviced. The second set of 50 control farms was matched by the veterinary practices which had provided case farms. Two separate analyses were conducted: (1) case farms (n=56) vs. randomly selected control farms (n=50) and (2) case farms (n=56) vs. a matched set of control farms (n=50). All variables with p<0.2 in the univariable analysis were included in stepwise logistic regression models. In the first analysis, only the use of PregSure(®) BVD vaccine was positively associated with BNP with an odds ratio of 1292 (95% CI: 114-14707). In the second analysis, conditional logistic regression models did not converge, therefore non-conditional logistic regression models were conducted. In the non-conditional analysis five variables remained in the model, three of which were negatively associated with BNP: the use of vitamin E and selenium, the frequent use of mastitis tubes, and the use of stem growth regulators in grain production. The use of prophylactic measures (such as control of parasites or vaccination of calves against respiratory disease) was positively associated with BNP with an odds ratio of 14.3 as well as the use of PregSure(®) BVD vaccine with an odds ratio of 426 (95% CI: 20-9095).
... Pour la plupart, ils sont idiopathiques, bien qu'ils soient parfois la conséquence d'une incompatibilité mère-foetus. Ils sont D epuis le début des années 2000, plusieurs dizaines de cas de syndrome hémorragique ont été décrits chez le veau nouveau-né, sans qu'une cause précise ne soit identifiée [8,27]. ...
... Les données publiées sur un syndrome hémorragique néonatal bovin semblent signaler une recrudescence des cas depuis 2007. En Allemagne, le nombre de cas de veaux atteints référés à la clinique des ruminants de l'université de Munich entre 2007 et 2009 équivaut à celui qui a été constaté antérieurement au cours des 26 dernières années (1981-2007, 89 cas) [8]. Depuis 2008 également, la Belgique semble connaître une augmentation des notifications [18]. ...
... Ce syndrome pourrait être sous-diagnostiqué, en lien avec la rapidité des lésions et la létalité associée. La totalité des cas décrits concernent des animaux de moins de 30 jours, de diverses races et sans lien génétique [1,8,12,18,20,[25][26][27][28][29][30]. Une déplétion périphérique des lignées blanche et rouge peut être mise en évidence. ...
