wetenschap Redactioneel De wetenschappelijke redactie van het Tijdschrift voor Diergeneeskunde is er trots op dat de diverse auteurs van dit artikel er voor gekozen hebben om hun bevindingen met betrekking tot het Schmallenbergvirus in het Tijdschrift voor Diergeneeskunde te publiceren en dat dit op zo korte termijn na de ontdekking al kon worden gerealiseerd. Eens te meer blijkt het belang van de gd Veekijker groot te zijn. Dit is een laagdrempelig contactpunt waar een dierenarts direct een ervaren collega aan de telefoon krijgt, eentje die wel over die praktijkgrenzen kan kijken en de juiste ingangen heeft bij de referentie-instituten. Proficiat voor de Gezondheidsdienst voor Dieren voor deze signalering, vervolgstappen en nu verslaglegging! Schmallenberg, waren we daar ooit niet eens op vakantie geweest? dr. Roel Boosman wetenschappelijke redactie Epizootic of ovine congenital malformations associated with Schmallenberg virus infection *i i R. van den Brom (dvm) , S.J.M. Luttikholt (MSc) , K. Lievaarti ii Peterson (dvm, PhD) , N.H.M.T. Peperkamp (dvm) , iii iv M.H. Mars (dvm, PhD) , W.H.M. van der Poel (dvm, PhD) i andP. Vellema (dvm, PhD) TijdschrDiergeneeskd2012:106-111 abstract Epizootic outbreaks of congenital malformations in sheep are rare and have, to the best of our knowledge, never been reported before in Europe. This paper describes relevant preliminary findings from the first epizootic outbreak of ovine congenital malformations in the Netherlands. Between 25 November and 20 December 2011, congenital malformations in newborn lambs on sheep farms throughout the country were reported to the Animal Health Service in Deventer. Subsequently, small ruminant veterinary specialists visited these farms and collected relevant information from farmers by means of questionnaires. The deformities varied from iDepartmentofSmallRuminantHealth,AnimalHealthService,Deventer, theNetherlands. IIDepartmentofPathology,AnimalHealthService,Deventer,theNetherlands. IIIDepartmentofDiagnostics,ResearchandEpidemiology,AnimalHealth Service,Deventer,theNetherlands. IVDepartmentofVirology,CentralVeterinaryInstitute,WageningenUniversity Research,theNetherlands. *Correspondingauthor:RenévandenBrom,dvm,DepartmentofSmall RuminantHealth,gd-AnimalHealthServiceDeventer,p.o.Box9,7400 aaDeventer,theNetherlands.E-mail:[email protected] 106 mild to severe, and ewes were reported to have given birth to both normal and deformed lambs; both male and female lambs were affected. Most of the affected lambs were delivered at term. Besides malformed and normal lambs, dummy lambs, unable to suckle, were born also on these farms. None of the ewes had shown clinical signs during gestation or at parturition. Dystocia was common, because of the lambs’ deformities. Lambs were submitted for post-mortem examination, and samples of brain tissue were collected for virus detection. The main macroscopic findings included arthrogryposis, torticollis, scoliosis and kyphosis, brachygnathia inferior, and mild-to-marked hypoplasia of the cerebrum, cerebellum and spinal cord. Preliminary data from the first ten affected farms suggest that nutritional deficiencies, intoxication, and genetic factors are not likely to have caused the malformations. Preliminary diagnostic analyses of precolostral serum samples excluded border disease virus, bovine viral diarrhoea virus, and bluetongue virus. In December 2011, samples of brain tissue from 54 lambs were sent to the Central Veterinary Institute of Wageningen University Research, Lelystad. Real-time pcr detected the presence of a virus, provisionally named the Schmallenberg virus, in brain tissue from 22 of the 54 lambs, which originated from seven of eight farms that had submitted lambs for post-mortem examination. This Schmallenberg virus was first reported in Germany and seems to be related to the Shamonda, Aino, and Akabane viruses, all of which belong to the Simbu serogroup of the genus Orthobunyavirus of the family Bunyaviridae. These preliminary findings suggest that the Schmallenberg virus is the most likely cause of this epizootic of ovine congenital malformations, which is the first such outbreak reported in Europe. Tijdschrift voor DiergeneeskundeDeel137Aflevering 21februari2012 wetenschap samenvatting Epizoötie uitbraak van congenitale afwijkingen bij schapen lammeren geassocieerd met infectie met het Schmallenbergvirus Epizoötische uitbraken van congenitale afwijkingen bij schapenlammeren zijn zeldzaam en zijn, voor zover we na hebben kunnen gaan, niet eerder beschreven in Europa. Dit artikel beschrijft de voorlopige relevante bevindingen van de eerste epizoötische uitbraak van congenitale afwijkingen bij lammeren in Nederland. Tussen 25 november en 20 december 2011 werden bij gd Veekijker Kleine Herkauwers congenitale afwijkingen bij lammeren gerapporteerd op schapenbedrijven verspreid over het land. Dierenartsen van de sector Kleine Herkauwers van de gd hebben de bedrijven bezocht en samen met de veehouder een vragenlijst ingevuld. De waargenomen congenitale afwijkingen varieerden van mild tot zeer ernstig. Het betrof zowel ram- als ooilammeren en in geval van meerlingen waren niet altijd alle lammeren in de worp afwijkend. De meeste lammeren werden na een normale draagtijd geboren. Naast afwijkende en normale lammeren, zijn ook ‘domme’ lammeren geboren die niet in staat waren om te drinken. Zowel tijdens de partus als gedurende de dracht zijn door de schapenhouders geen klinische verschijnselen aan de ooien waargenomen, anders dan dystocia ten gevolge van afwijkende lammeren. Lammeren zijn ingestuurd voor pathologisch onderzoek en hersenweefselmonsters zijn verzameld voor virologisch onderzoek. De belangrijkste macroscopische bevindingen waren arthrogrypose, torticollis, scoliose, kyphose, brachygnathia inferior en geringe tot ernstige hypoplasie van grote en kleine hersenen en het ruggenmerg. Gebaseerd op de voorlopige onderzoeksresultaten van de eerste tien bedrijven lijken mogelijke oorzaken van congenitale afwijkingen bij lammeren zoals voedingsdeficiënties, intoxicaties en genetische factoren, onwaarschijnlijk. Voorlopige resultaten van aanvullend onderzoek op precolostrale sera sluiten border disease virus, bovine virus diarree virus en bluetongue virus uit als mogelijke oorzaak. In december zijn hersenweefselmonsters van 54 lammeren opgestuurd naar het Centraal Veterinair Instituut, Wageningen University Research, Lelystad. Door middel van een ‘real-time’ pcr werd een virus, dat voorlopig Schmallenbergvirus wordt genoemd, aangetoond in de hersenen van 22 van de 54 lammeren, afkomstig van zeven van de acht bedrijven die lammeren voor pathologisch onderzoek hadden ingestuurd. Dit Schmallenbergvirus is voor het eerst beschreven in Duitsland en lijkt het meest verwant aan het Shamonda-, Aino- en Akabanevirus die alle behoren tot de Simbuserogroep van het genus Orthobunyavirus van de familie Bunyaviridae. Deze voorlopige bevindingen geven aan dat het Schmallenbergvirus de meest waarschijnlijke oorzaak is van de waargenomen epizoötische uitbraak van congenitale afwijkingen bij lammeren die nooit eerder in Europa is beschreven. introduction Congenital malformations occur in different animal species, including ruminants (1). The incidence of such malformations has been reported to be 0.2-2.0% in newborn lambs in Australia (2). Possible causes of congenital malformations in sheep are genetic factors (3-5), teratogenic plants (6-8), nutritional deficiencies (9, 10), and teratogenic viruses (11-31). Cases of ovine congenital malformations were first reported to the Dutch Animal Health Service (Gezondheidsdienst voor Dieren, gd) on 25 November 2011. On 9 December, veterinary Tijdschrift voor DiergeneeskundeDeel137Aflevering 21februari2012 Figure 1. The location of the 30 farms (red and blue dots) that reported malformed lambs between 25 November and 20 December 2011. Thereddotsindicatethefirsttenfarmsthataredescribedin moredetail.On1January2012,morethan60sheepfarms havereportedthebirthofmalformedlambs. practitioners were informed and invited to report further cases to the gd, and on 20 December disease manifestations were made notifiable in the Netherlands. This paper describes preliminary findings from the first ten farms on which malformed lambs were born, and the epizootic characteristics of these malformations. materials and methods Sheep farmers reporting cases of ovine congenital malformations were invited to submit lambs for post-mortem examination to the gd. A questionnaire was drafted and farms were visited by veterinarians from the gd specialized in small ruminant health. This paper describes the preliminary observations, gross pathology, and laboratory results of lambs from the first ten farms affected. A questionnaire was used to obtain epidemiological and clinical information during farm visits. The questionnaire consisted of three parts. The first part focused on general farm information, including the number of sheep, breeds, animal movements, other animal species on the farm, and possible contact with other animals, with special attention for other ruminants. The second part consisted of questions related to the health status, feeding regimen, vaccinations performed, and drugs used. The third part consisted of questions regarding the current breeding and lambing season and included questions 107 wetenschap Picture 1. A lamb with congenital malformations: arthrogrypo- Picture 2. A lamb with congenital malformations: scoliosis and sis, kyphosis, and brachygnathia inferior. about oestrus synchronization, age, breed, number, and origin of the rams used, flock fertility, the start of the lambing season, timing of births of lambs with malformations, ewe health status, and malformations of the lambs. Blood samples were collected from ewes that had given birth to malformed lambs (maximum five samples per farm), and from malformed lambs. Samples were tested for border disease virus (bdv)/bovine viral diarrhoea virus (bvdv) (Priocheck ® bvdv Ab, Prionics AG, Switzerland; idexx bvdv Ag/Serum Plus Test, idexx Laboratories, Inc., Westbrook, Maine, u.s.a.), and bluetongue virus (btv) (idexx Bluetongue Competition Ab Test, idexx Laboratories, Inc., Westbrook, Maine, u.s.a.). The farmers were asked to submit lambs with malformations for post-mortem examination. Foetal blood, brain, and muscle samples and, if available, placental membranes, were stored for future investigation. Brain tissue samples were tested at the national reference laboratory, the Central Veterinary Institute (cvi), Lelystad, the Netherlands, using a real-time pcr developed by the Friedrich Loeffler Institute (fli). Number of submitted lambs torticollis. The assay targets the L segment of a virus provisionally named the Schmallenberg virus, a virus from the genus Orthobunyavirus of the family Bunyaviridae (32). results The preliminary gross pathology findings and the location of the reported farms with malformed lambs are presented in Table 1 and Figure 1. Preliminary findings from the first ten farms to report congenital malformations, before disease manifestations were made notifiable, are described in further detail. On farm A, a ewe gave birth to a malformed lamb of approximately 115 days’ gestation with arthrogryposis and hydranencephaly. This ewe was bought from farm B at approximately 100 days’ gestation. No lambs had been born on farm B at the time of reporting of the first case on farm A; however, the farmer reported that some of his ewes, found pregnant by ultrasonographic scanning earlier, seemed barren later on. From 6 December onwards, farms C, D, E, and F reported congenital A B C D E F G H I J 3 - 12 14 14 - 2 5 3 2 Number of submitted lambs with multiple defects 2 - 10 12 9 - 2 5 3 2 25 Nov 25 Nov 6 Dec 7 Dec 8 Dec 9 Dec 12 Dec 13 Dec 14 Dec 14 Dec Arthrogryposis * - * * * - * * * * Torticollis * - * * * - * - * * Kyphosis * - * * * - - * * - Scoliosis * - * * * - * * * * Brachygnatiainferior - - * * * - - * * * Micro-/hydranencephaly * - * * - - * * - * Hypoplasiacerebrum - - - - * - - - * - Cerebellarhypoplasia * - * * * - * * * * Hypoplasiaspinalcord * - * * * - * * * - Date of reporting Table 1. Gross pathology findings of 55 lambs on the first ten reported farms (A to J), submitted between 25 November and 20 December 2011 for post-mortem examination. *:symptompresent -:notsubmittedorsymptomnotpresent 108 Tijdschrift voor DiergeneeskundeDeel137Aflevering 21februari2012 wetenschap malformations in lambs. Farm F reported two malformed lambs out of four newborn, but did not submit lambs for post-mortem examination. During the first 3 days of the following week, malformed lambs were reported on farms G, H, I, and J. The most pronounced malformations were arthrogryposis of all legs with skeletal muscle dysplasia and deformities of the cervical and thoracic vertebral column. The deformities varied from mild to severe, affected both male and female lambs, and some ewes with multiple lambs had given birth to both normal and deformed lambs. Most of the affected lambs were delivered at term; some lambs were stillborn, and a few severely deformed lambs were born alive. Most of these lambs were not able to stand or suckle. Besides malformed and normal lambs, dummy lambs were born that were unable to suckle. Some farmers reported blindness and abnormal behaviour. None of the farmers reported clinical signs in the pregnant ewes at delivery or earlier during gestation, with the exception of dystocia at parturition due to the lambs’ deformities. Many ewes required assistance at parturition and some died as a consequence of uterine perforation. None of the people living or working on the affected farms have reported clinical signs. Affected farms had 10-600 sheep and animals did not come into frequent contact with other species. The breeds on affected farms included the white and blue Texel, Suffolk, Frisian Milk Sheep, Flevolander, Swifter, Blessumer, Rouge de L’Ouest, and crossbreds. While many farms had carried out vaccination and treatment programmes in the same year, no single vaccine or medication was used on all affected farms. The flocks were healthy and had mainly grazed without supplementary feeding during the breeding season and early gestation. On some farms the ewes were synchronized. Different breeds of rams had been used and some had also been used in preceding years. Fertility rates were lower in some flocks, but higher rates of abortion had not been reported. Ewes of different ages gave birth to malformed lambs. Four of the farms had also had a lambing period in October and/or November, and none of the lambs had had congenital malformations. The main macroscopic changes were arthrogryposis (Picture 1), torticollis (Picture 2), scoliosis (Picture 2), kyphosis (Picture 1), brachygnathia inferior (Picture 1), and various degrees of hypoplasia of the central nervous system (Pictures 3 and 4), resulting in microcephaly, hydranencephaly, cerebellar hypoplasia, and hypoplasia of the spinal cord. Preliminary diagnostic analyses of blood samples from ewes and living malformed lambs and precolostral serum samples from lambs submitted for post-mortem examination excluded bdv, bvdv, and btv. Eight farms submitted lambs for post-mortem examination. The Schmallenberg virus real-time pcr was positive in brain tissue samples from 22 of 54 lambs originating from seven of eight affected farms.. discussion Ovine congenital malformations are not uncommon, but usually only a few cases occur per farm (3, 33). Multiple cases of congenital malformations on a farm may indicate a genetic background, such as the inherited limb deformity called spider lamb in pedigree Suffolk lambs (4), or the presence of teratogenic plants (8) or nutritional deficiencies (9, 10, 34). Teratogenic viruses can cause epizootic outbreaks of congenital malformations in lambs on several farms with different breeds, different management practices, and in a larger geographic area. Such outbreaks are rare, but have been reported in Japan, Australia, Israel, North America, and Africa (20, 21, 23-31). Picture 3. Hypoplasia of the central nervous system: cerebellar hypoplasia. Tijdschrift voor DiergeneeskundeDeel137Aflevering 21februari2012 109 wetenschap Picture 4. Hypoplasia of the central nervous system: microcephaly, hydranen- cephaly, cerebellar hypoplasia. In Europe, epizootic outbreaks of ovine congenital malformations have, to the best of our knowledge, never been reported. The affected farms were located throughout the Netherlands, different breeds were involved, and pregnant ewes did not show symptoms of disease. Not all farms applied oestrus synchronization or used the same vaccines or drugs. Feeding patterns, apart from grazing, were also different on the different farms. Taking this information into consideration, it would seem unlikely that a genetic background, teratogenic plants, nutritional deficiencies, or teratogenic effects of vaccines or drugs are a possible cause of these congenital malformations. bdv, bvdv, and btv are the most plausible teratogenic viruses in the Netherlands, and although a recent serological study demonstrated a pestivirus prevalence of 45% in sheep in the Netherlands (35), this causal agent could be excluded. btv-8 has been demonstrated to cause hydranencephaly in cattle and sheep (13, 14), and although btv has not been detected in the Netherlands since 2008, it was necessary to exclude this viral agent as a possible cause. The fact that none of the farmers reported clinical signs in the pregnant ewes during gestation or at parturition was consistent with this virus not being the causative agent. The next group of viruses reported to cause congenital malformations in sheep are viruses of the genus Bunyaviridae. Epizootic outbreaks caused by viruses of this family, such as Akabane, Cache Valley, Main Drain, San Angelo, Lacrosse and Rift Valley fever virus have been reported in Japan, Australia, Israel, America, and Africa (20, 21, 23-31), and seroprevalence without clinical features has been described in Cyprus (36) and Turkey (37). Using brain samples, in 22 of 54 affected lambs originating from seven of eight different farms, we detected a virus provisionally named the Schmallenberg virus. On the basis 110 of its rna sequences, this virus seems most likely related to the Shamonda, Aino and Akabane viruses, which all belong to the Simbu serogroup of the genus Orthobunyavirus of the family Bunyaviridae (32). In conclusion, a virus of the genus Orthobunyavirus, provisionally called Schmallenberg virus, is regarded as the most likely cause of the epizootic outbreak of ovine congenital malformations. This is the first report of such malformations in Europe. acknowledgements Monitoring of small ruminant health in the Netherlands is financially supported by the Dutch Ministry of Economic Affairs, Agriculture and Innovation (el&i) and the Product Board for Livestock and Meat (pvv). We would like to thank our colleagues, both at the Animal Health Service (gd) and the Central Veterinary Institute (cvi), sheep farmers, and veterinarians who kindly provided information and submitted lambs for post-mortem examination. We also want to thank M. Beer and B. Hoffmann of the Friedrich Loeffler Institute, Riems, Germany, for kindly sharing their rt-pcr assay for detection of the Schmallenberg virus. 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