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Clinical Description and Epidemiology (Schelcher et al., 2010)

The disease affects calves less than 1 month old. Characteristic lesions are haemorrhages and/or multifocal petechiae. Associated clinical signs are, in order of frequency: hyperthermia above 39.8°C, haemorrhagic fecal discharge, petechiae on the mucous membranes, blood sweating (40% of cases), increased bleeding time (especially at injection sites and associated with identification loops), paleness of the mucous membranes and polypnoea. More than 90% of affected calves show a progressive breakdown and die within 72 hours. Differential diagnosis includes BVD virus infection, some bacterial septicaemia, eagle fern or K-anti-vitamin poisoning, and other less frequent poisonings. The complementary tests of choice are the blood count and myelogram. Animals show severe thrombocytopenia (<100,000 platelets/mm3) associated with leukopenia (<5,000 leukocytes/mm3), as well as subtotal to total bone marrow aplasia. At the end of their evolution, animals may present anemia due to multifocal haemorrhages. At necropsy, the animals present multiple haemorrhages (digestive tract, subcutaneous tissue, meninges...). All breeds are affected.
Approximately 4000 cases of BNP have been reported to date in Europe. The prevalence of the disease is therefore relatively low. Moreover, the prevalence of the disease within a herd would not usually appear to exceed 10% (Bastian et al., 2011), although some herds are exceptionally faced with a higher prevalence. It appears that some calves, so-called subclinical calves, of the same age as the sick calves, do not report the disease but show haematological alterations (Théron et al., 2010).

Etiological hypotheses and biological mechanisms 

Among the cases identified as probably suffering from bovine neonatal pancytopenia, vaccination with Pregsure® vaccine of the dams of case calves was identified in a very high proportion. A link was also suspected with colostrum, with cases appearing to be dependent on this ingestion.
The BNP syndrome has been experimentally reproduced on newborn calves deprived of colostrum and given colostrum from mothers that gave birth to calves with BNP (Friedrich et al, 2011). Reproduction was achieved in 4 out of 6 calves, confirming the role of colostrum as a vector and suggesting a dose-related effect (e.g. amount of antibodies). Subsequently, reproduction was carried out by injecting purified immunoglobulins from cows that had previously given birth to a BNP calf (Foucras et al, 2011). Reproduction was then systematic, confirming the role of colostrum as an antibody vector. The question remained as to which ones?
These "toxic" antibodies recognize an allele of the major histocompatibility complex type 1 (MHC1). This allele is present on calf cells (white blood cells, thrombocytes, bone marrow stem cells) with BNP, and also in quantities in the cell line used to produce the Pregsure® vaccine. The MHC1 antigen of the mothers of BNP calves would be mutated (hypothesis under analysis) compared to the MHC1 contained in the vaccine (which would contain the wild allele). The injection of the vaccine into certain cows would then lead to the production of antibodies recognizing the wild allele (Deutskens et al, 2011, Foucras et al, 2011).
The cases of BNP can then be explained by the presence of the wild allele in the calf, from one of the two parents (certainly the father), targeted and destroyed by the antibodies produced by the mother in reaction to the vaccination. These results were confirmed by two research teams in Germany and France (Toulouse) (Deutskens et al, 2011, Foucras et al, 2011).
The mechanism identified thus clearly has an immune and a genetic axis. The very nature of the mechanism suggests that other vaccines (including with other viral antigens) could be involved (Foucras et al, 2011).

 What to do in a case of BNP

There is no known effective treatment for the disease. Studies have reported that a cow that has given birth to a calf that has developed the disease has an increased risk of having a sick calf at the next calving.
The following advice is recommended for colostrum administration on farms where a case of BNP has occurred:

• Producers should avoid using a mixture of colostrums from several cows (especially if it contains colostrum from a cow that gave birth to a calf with BNP).
• Farmers must ensure that newborn calves, born to mothers who have previously given birth to a calf with a BNP, do not have access to their mothers' colostrum; farmers must ensure that these calves receive a sufficient quantity of colostrum from cows that have not had a calf with a BNP, and in a timely manner.
• On farms where BNP has occurred, it is advisable to collect and store colostrum from cows that have not given birth to a calf with BNP to ensure that colostrum is available.
• In herds with a high incidence of BNP, colostrum from another herd without a BNP case may be sought. In this situation, a risk/benefit assessment should be made with the client regarding the risk of BNP and the risk of disease transmission or other potential problems due to the use of "foreign" colostrum.

References

• Bastian M., Holsteg M., Hanke-Robinson H., Duchow K., Cussler K. Bovine Neonatale Pancytopenia : is this alloimmune syndrome caused by vaccine-induced alloreactive antibodies ? Vaccine 2011. 29 : 5267-5275
• Deuskens F., Lamp B., Riedel C.M., Wentz E., Lochnit G., Doll K., Thiel H.J., Rümenapf T. Vaccine-induced antibodies linked to bovine neonatal pancytopenia (BNP) recognize cattle major histocompatibility complex class I (MHC I). Veterinary Research. 2011. 42:97
• Foucras G., Corbière F., Tasca C., Pichereaux C., Caubet C., Trumel C., Lacroux C., Franchi C., Burlet-Schiltz O., Scelcher F. Alloantibodies against MHC class I : a novel mechanism of neonatal pancytopenia linked to vaccination. The journal of immunology. 2011. 10 40:49
• Sauter-Louis C., Carlin A., Friedrich A., Assad A., Reichmann F., Rademacher G., Heuer C., Klee W. Case control study to investigate risk factors for bovine neonatal pancytopenia (BNP) in young calves in southern Germany. Preventive Veterinary Medicine. 2012. In press
• Scelcher F, Franchi C, Corbière F, Lacroux C, Maillard R, Meyer G, Trumel C, Eloit M. Pancytopénie Néonatale Bovine : description d’une nouvelle maladie. Le point vétérinaire. Sept 2010. N° 308. p50.
• Bridger PS, Bauerfeind R, Wenzel L, Bauer N, Menge C, Thiel HJ, Reinacher M, Doll K. Detection of colostrum-derived alloantibodies in calves with bovine neonatal pancytopenia. Vétérinary Immunology and Immunopathology In press (2010), doi : 10.1016/j.vetimm.2011.01.001.
• Théron L, Vogin N, Moreau E, Bayrou C, Rollin F, Hanzen C. La pancytopénie néonatale bovine : un nouveau syndrome. Le point vétérinaire. (2010) Vol 41. p79-85.
• Friedrich A, Büttner M, Rademacher G, Klee W, Weber BK, Müller M, Carlin A, Assad A, Hafner-Marx A, Sauter-Louis CM. Ingestion of colostrum from specific cows induces Bovine Neonatal Pancytopenia (BNP) in some calves. BMC Veterinary Research. 2011 Feb 18;7:10.

References