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October 25, LECTUER-6 INFECTIOUS DISEASES 2016 Week No: 5 L. Dr. Yahia I. Khudair ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Bovine virus diarrhea - Mucosal disease (BVD-MD) The bovine viral diarrhea (BVD) virus causes a number of disease syndromes in cattle. It was first recognized in North America in the 1940s, the disease is complex infection can cause diarrhea, fever, abortion and reduced fertility. Calves may be born weak and stunted calves, they may also be born with brain and eye abnormalities and lesions on nose and mouth. Etiology Bovine Virus Diarrhoea (BVD) and Mucosal Disease (MD) are caused by a the viruses are classified in the virus family Flaviviridae and are members of the genus pestivirus. Pestiviruses are nonsegmented, single, sense stranded RNA viruses, there are two biotypes designated depending on their effect on tissue culture cells for non-cytopathic (NCP): The noncytopathic type is the most common and most important. the non-cytopathic type crosses the placenta, invades the fetus and establishes persistent infection in the fetus, which is crucial for spread of the virus. It is the cause of a wide range of congenital, enteric and reproductive diseases. cytopathic (CP): the cytopathic biotype of the virus is usually associated with only mucosal disease in animals already persistently infected with the non-cytopathic biotype. (There is considerable antigenic diversity and antigenic cross-reactivity among isolates of BVDV which has implications for diagnostic testing and for control by vaccination) EPIDEMIOLOGY Occurrence The virus is widespread in cattle herds worldwide and locally. The prevalence of infection is high but the incidence of clinical mucosal disease is low. The BVDV causes several different diseases including: Benign bovine virus diarrhea, which is usually subclinical Fatal mucosal disease which occurs in persistently viremic animals and those specifically immunotolerant as a result of an infection acquired in early fetal life Peracute, highly fatal diarrhea Thrombocytopenia and hemorrhagic disease Reproductive failure Congenital abnormalities in calves as a result of fetal infection in mid gestation. The virus may also be immunosuppressive. Page 1 October 25, LECTUER-6 INFECTIOUS DISEASES 2016 Week No: 5 L. Dr. Yahia I. Khudair ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Young cattle which are persistently infected with a non-cytopathic strain of the virus are the major source of infection in a herd. So the mucosal disease occurs only in PI animals as a result of a congenital infection with a non-cytopathic strain of the virus acquired in early fetal life. These animals remain specifically immunotolerant to the homologous strain of the BVDV throughout postnatal life, and fatal mucosal disease is precipitated by a superinfection with a cytopathic strain of the virus occurring usually at 6-24 months of age or older. Morbidity and case-fatality rates Mucosal disease in PI immunotolerant seronegative animals occurs in all classes of cattle mostly between 6 and 24 months of age, rarely in calves as young as 4 months of age, or cattle older than 2 years of age. Methods of transmission The major source of infection is the PI viremic animal. The virus can be isolated from nasal discharge, saliva, semen, feces, urine, tears and milk, each of which would allow wide dissemination of the virus. Herds become infected by contact with infected animals, especially with so-called carrier animals. Artificial insemination and embryo transfer can spread pestivirus. Although cattle are the primary hosts, pigs, sheep, alpacas and wild ruminants such as deer may also carry the virus. Direct contact The virus is transmitted by direct contact between animals, and by transplacental transmission to the fetus. Discharges from the reproductive tract of an infected cow, either PI or systemically immune, including Aborted fetuses can be potent sources of the virus. Nose-to-nose contact is an effective method of transmitting the virus from PI to susceptible animals. PI animals may introduce the infection into a herd, or when infected animals are mixed with susceptible animals at the time of breeding. Transmission of the virus between healthy immunocompetent animals is probably insignificant because they produce antibodies and eliminate the virus Indirect contact Page 2 October 25, LECTUER-6 INFECTIOUS DISEASES 2016 Week No: 5 L. Dr. Yahia I. Khudair ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Airborne transmission. Indirect airborne transmission of the virus can occur in calves housed near a PI calf for one week at distances of 1.5 and 10 m – without having direct contact with a PI calf. Flies. The virus has been experimentally transmitted by allowing blood feeding flies to feed on a PI animal followed by feeding on BVDV-free seronegative recipients. Fomites. The BVDV has been transmitted from a PI animal to susceptible heifers which were examined per rectum using the same glove. Reusing a hypodermic needle on susceptible animals or reusing a nose tong after it had been used on a PI animal could also transmit the infection. Risk factors Animal risk factors Young cattle are most susceptible to BVDV infection but adult cattle may develop severe disease if infected with the highly virulent genotypes of the virus. Persistent infection can be established only in the first half of fetal life. Unvaccinated animals, improperly vaccinated animals, or animals whose immune status has waned are most susceptible to infection and the potential for clinical disease. PI animals are susceptible to the development of mucosal disease following superinfection with the cytopathic virus. Environmental and management risk factors The major management risk factors are the introduction of PI animals into a susceptible herd and the failure of a vaccination program or an inadequate vaccination program. Pathogen risk factors The bovine pestivirus is one of the most widespread and important virus infections in cattle throughout the world. While only one serotype of BVDV is recognized, isolates of these viruses vary genomically, antigenically and biotypically, Antigenic diversity. BVDV is subject to genomic modifications that involve point mutations or recombination of RNA and thus are highly mutable, the high frequency of mutation, propensity for recombination, and selective pressure from immune responses stimulated by natural infection or vaccination has led to the creation of a large assortment of genetic and Page 3 October 25, LECTUER-6 INFECTIOUS DISEASES 2016 Week No: 5 L. Dr. Yahia I. Khudair ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, antigenic variants of the virus. The consequences of diversity include diversity of clinical disease, diagnostic difficulties, and vaccination failures. Non-cytopathic and cytopathic BVD virus biotypes. Bovine viral diarrhea viruses exist as non-cytopathic or cytopathic biotypes. Non-cytopathic biotypes produce little if any visible cytopathic change in cell cultures, and infected cells generally appear normal. Cytopathic biotypes, in contrast, cause cellular vacuolation and cell death The BVDV is maintained in the environment by PI animals which were infected by non cytopathic virus in utero from 42-125 d of gestation, when their immune system does not recognize the persisting virus as foreign and the animal is said to be immunotolerant. Mucosal disease is the result of PI animals being superinfected with a cytopathic virus that is antigenic ally similar to the persisting non-cytopathic virus and both types are isolated from cattle with mucosal disease PATHOGEN ESIS The pathogenesis depends on multiple interactive factors. Host factors which influence the clinical outcome of BVDV infection include: Whether the host is immunocompetent or immunotolerant to the virus Age of the animal Transplacental infection and gestational age of the fetus Induction of immune tolerance in the fetus and the emergence of fetal immune competence at about 180 d of gestation Immune status (passively derived or actively derived from previous infection or vaccination) Presence of stressors. Genetic diversity among isolates may account for differences in the clinical response to infection. There is a spectrum of clinical responses based on the host factors and the virulence of the isolates involved. Immunocompetent non-pregnant cattle: Page 4 October 25, LECTUER-6 INFECTIOUS DISEASES 2016 Week No: 5 L. Dr. Yahia I. Khudair ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Subclinical BVDV This is a subacute infection in seronegative, immunocompetent cattle usually after colostral immunity has waned and it occurs in both sexes and any class of cattle. It is usually a clinically unrecognizable infection with the development of serum-neutralizing (SN) antibodies and elimination of the virus from normal immunocompetent animals. A mild transient clinical disease characterized by inappetence for a few days, depression, fever, mild diarrhea, transient leukopenia and recovery in a few days may occasionally occur. In some cases, outbreaks of diarrhea occur in animals ranging from 6 months to 1 year of age, characterized by high morbidity and low or no mortality. Peracute bovine virus diarrhea A severe and highly fatal form of bovine virus diarrhea associated with noncytopathic Type II isolates of the BVD virus outbreaks were most common in dairy herds with inadequate vaccination programs and which recently introduced animals into the herd Thromboctyopenia and hemorrhagic syndrome Thrombocytopenia and the hemorrhagic syndrome occurs in adult cattle and calves affected with the peracute form of BVDV infection. Platelet counts are reduced to below 25 000 / lL, and clinically are bloody diarrhea, petechial and ecchymotic hemorrhages of the sclera of the eyes, epistaxis and abnormal bleeding from injection sites. Hyphema may also occur. Thrombocytopenia due to destruction of platelets Meningoencephalitis A type 2 BVDV strain has been isolated from the brain tissue of 15-month-old heifer with neurological clinical findings and pathologic evidence of multifocal meningoencephalitis Immunosuppression There is evidence that postnatal BVDV infections of cattle can cause immunosuppression and enhance the development of other infectious diseases. Ovarian dysfunction Ovarian dynamics may be changed in cattle infected with BVDV. Ova exposed to the cytopathic BVDV effects on survivability of blastocyts. Bovine follicular cells and oocytes are permissive to BVDV at all stages of follicular development Immunocompetent pregnant cattle and fetal infections The BVDV can cause significant early reproductive loss in non-immune pregnant cattle including fertilization failure, embryonic mortality and abortion. In addition, infection of the fetus between 42 and Page 5 October 25, LECTUER-6 INFECTIOUS DISEASES 2016 Week No: 5 L. Dr. Yahia I. Khudair ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 125 d of gestation may result in persistently-infected fetuses which are carried to term and the calf may be born alive and thrive normally or be unthrifty. The BVDV can cause reproductive failure in susceptible cattle during the following stages of the reproductive cycle: 1- Infection prior to insemination. Exposure of cattle to the virus during the estrus cycle prior to insemination can result in a decrease in conception rate due to failure of ovulation or delayed ovulation. PI cows may have morphologic changes in their ovaries suggesting a reduction in normal ovarian activities 2- Insemination of cattle with semen containing bovine pestivirus. The insemination of seronegative and virus-free heifers with BVDVcontaminated semen can result in poor conception rates initially. 3- Infection during embryonic period: 0-45 d gestation. Natural BVDV infection of seronegative heifers 4 days after insemination results in viremia between 8 and 17 d and a decrease in conception rate and pregnancy rate compared to uninfected heifers.26 Infected heifers which fail to conceive return to estrus approximately 20 d later Fetal infections 4. Infection during late embryonic-early fetal period: 45-125 d gestation. Following the infection of a non-immune pregnant animal the virus is capable of crossing the placental barrier and invading the fetus. Fetal infection can result in a wide spectrum of abnormalities from death of the fetus to congenital defects, to a persistent infection of the fetus until term and birth of a calf with lifelong infection without clinical signs. The results are mainly dependent on the stage of fetal development at which infection takes place. In general, the risk for the fetus is highest during early pregnancy. Infection of the fetus from 50-100d of gestation may result in fetal death and abortion from days to several months after fetal infection or mummification. 5- Persistent viremia and mucosal disease. One of the most important effects of BVDV infections of the fetus is the development of PI animals. Following infection of the fetus with a non-cytopathic isolate of the virus from about 45-125 d of gestation, it may be carried normally to term and be born with a persistent infection. Mucosal disease occurs in aproportion of these, and only in these PI animals. from birth to the time of clinical disease, which usually occurs between 6 and 24 months of age, and Page 6 October 25, LECTUER-6 INFECTIOUS DISEASES 2016 Week No: 5 L. Dr. Yahia I. Khudair ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, rarely up to 3 years of age, these animals are persistently viremic and specifically immunotolerant to the homologous strain of the persisting virus. They may appear clinically normal or unthrifty and small for their age. Occasionally, PI cattle may survive and remain healthy for up to 5 years during which time they shed the virus in their mucous secretions and may be seropositive to a range of BVDV strains. The pathogenesis of the lesions of mucosal disease remains obscure many tissues including: Lymph nodes, Peyer's patches, Ileum and lymphoid tissue in the proximal colon, Palatine tonsils, Spleen and Tongue, Esophagus, Skin. The pathological changes which characterize the disease involve the integument and the epithelia of the respiratory and alimentary tracts as well as lymphoid tissues. The basic lesion is a small vesicle ulcer which affects only epithelial cells. The erosions occur throughout the: Oral cavity, Esophagus, Forestomachs, Abomasum, Small intestine, Cecum and Colon. Infection during fetal period 125-175 d gestation. Congenital defects: Transplacental infection of the fetus approximately between 125-175 d of gestation can result in numerous congenital defects, this period of development corresponds to the final stages of organogenesis of the nervous system and the development of the fetal immune system, which can result in the generation of an inflammatory response to the virus. Cerebellar hypoplasia occurs and ocular abnormalities consist of retinal atrophy, optic neuritis, cataract, and microphthalmia with retinal dysplasia. Calves with cerebellar hypoplasia are unable to stand and walk normally immediately after birth. Defects of the eyes result in varying degrees of blindness Infection during fetal period between 180 d gestation and term. Infection of the fetus with the BVDV after approximately 150 d gestation results in a fully competent immune response and elimination of the virus. At birth, the fetus has antibody to the virus but is virus free. The effects of late-gestation infections are not well documented but abortions, stillbirths, and weak calves are reported. CLINICAL FINDINGS Inapparent or subclinical infection (bovine virus diarrhea) Page 7 October 25, LECTUER-6 INFECTIOUS DISEASES 2016 Week No: 5 L. Dr. Yahia I. Khudair ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The most frequent form of BVDV infection in cattle is non -clinical or a mild disease of high morbidity and low case fatality characterized by a mild fever, leukopenia, inappetence and mild diarrhea followed by rapid recovery in a few days and the production of virusneutralizing antibodies. The acute mucosal disease The disease is characterized by the sudden onset of clinical disease in animals from 6- 24 months of age which were infected during early fetal life. The morbidity is low and the case-fatality rate is high (over 90%) Affected animals are depressed, anorexic and drool saliva, wetting hair around the mouth. Fever 40-41 C, tachycardia and polypnea are common. Ruminal contractions are usually absent and a profuse and watery diarrhea occurs 2-4 d after the onset of clinica 1 illness. The feces are foul smelling and may contain mucus and variable quantities of blood, small tags of fibrinous intestinal casts are present. Straining at defecation is common and the perineum is usually stained and smeared with feces. Lesions of the oral cavity mucosa consist of discrete, shallow erosions which become confluent, resulting in large areas of necrotic epithelium becoming separated from the mucosa. These erosions occur: Inside the lips On the gums and dental pad On the posterior part of the hard palate At the commissures of the mouth On the tongue. The entire oral cavity may have a 'cooked' appearance with the grayish colored necrotic epithelium covering the deep-pink, raw base. Similar lesions occur on the muzzle and may become confluent and covered with scabs and debris. Although the oral lesions are significant in the identification of the disease, they may be absent or difficult to see in up to 20% of the affected animals. There is usually a mucopurulent nasal discharge associated with some minor erosions on the external nares and similar lesions in the pharynx. Lacrimation and corneal edema are sometimes observed. Page 8 October 25, LECTUER-6 INFECTIOUS DISEASES 2016 Week No: 5 L. Dr. Yahia I. Khudair ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Lameness occurs in some animals and appears to be due to laminitis, coronitis and erosive lesions of the skin of the interdigital cleft, which commonly affect all four feet. Dehydration and weakness are progressive and death occurs 5-7 d after the onset of signs. In peracute cases, which die within a few days after the onset of illness, the diarrhea may not be evident even though the intestines are distended with fluid. Presumably, there is paralytic ileus and the intestinal fluid is not moved down the intestinal tract. Chronic mucosal disease Some acute cases of mucosal disease do not die within the expected time of several days and become chronically ill. There may be intermittent bouts of: Diarrhea Inappetence Progressive emaciation Rough dry hair coat Chronic bloat Hoof deformities Chronic erosions in the oral cavity and on the skin. Shallow erosive lesions covered with scabs can be found on the perineum, around the scrotum, preputial orifice and vulva, between the legs and at the skin horn junction around the dew claws, in the interdigital cleft and at the heels, and there may be extensive scurfiness of the skin. The failure of these skin lesions to heal is an important clinical finding suggesting chronic mucosal disease. Chronic cases will sometimes survive for up to 18 months during which time they Unthrifty PI calves Peracute bovine virus diarrhea It is severe of the enteric form of the disease; it is often highly fatal, occurs in immunocompetent seronegative cattle in postnatal life and is associated with highly virulent isolates of the Type II virus. The most common complaint given by the owners was the presence of respiratory disease in affected animals. The outbreaks were slowly progressive and lasted for several weeks. Severe depression, respiratory distress, anorexia, profuse watery diarrhea, dysentery, conjunctivitis, fever up to 42.0°C, and agalactia in adult lactating dairy cows were common. Oral erosions were inconsistent. Abortion Usually in late gestation, was a common but inconsistent occurrence. Morbidity rates may be up to 40% and crude mortality rates may reach 25 % . Many animals may die within a few Page 9 October 25, LECTUER-6 INFECTIOUS DISEASES 2016 Week No: 5 L. Dr. Yahia I. Khudair ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, days after the onset of clinical signs, and persistently infected calves were commonly born several months following the outbreaks. Thrombocytopenia and hemorrhagic disease Thrombocytopenia and hemorrhagic disease have been associated with BVDV, bloody diarrhea, petechial and ecchymotic hemorrhages of the visible 'mucosae, hyphema, epistaxis and prolonged bleeding from injection sites or insect bites have been observed. Cattle have platelet counts of less than 25 000/µ1 and clinically there is bloody diarrhea. Fever, diarrhea, rumen stasis and dehydration are also common. The case fatality rate is approximately 25% Reproductive failure and neonatal The infection during the embryonic early- to mid-fetal period can result in conception failure, increased embryonic mortality, fetal mummification, abortion, premature births, stillbirths, congenital defects, the birth of stunted weak calves, and the birth of PI calves which subsequently may develop mucosal disease CLI NICAL PATHOLOGY The clinical diagnosis of mucosal disease is usually made on the basis of the presence of characteristic clinical and pathological findings. A severe leukopenia is characteristic of acute mucosal disease. The decrease is commonly to below 50% of normal and total leukocyte counts of 1000-3000/pL are common and m ay persist for weeks. Virus isolation Antigen detection Immunohistochemistry. The BVDV antigen can be identified rapidly in tissue samples using immunohistochemical methods such as immunofluorescence or immunoenzyme staining in sections of frozen tissue, Polymerase chain reaction (PCR) Serology Serological techniques are used to detect and measure antibodies. The serum neutralization antibody(SN), ELISA Differential diagnosis Bovine malignant catarrh. Rinderpest. Infectious bovine rhinotracheitis (lBR), Diseases causing diarrhea with no oral lesions include Winter dysentery, salmonellosis, Johne's disease, molybdenum poisoning (conditioned copper deficiency), parasitism (ostertagiasis), and arsenic poisoning. • Thrombocytopenia and hemorrhagic disease. Malignant catarrhal fever. Moldy sweet clover poisoning Page 10 October 25, LECTUER-6 INFECTIOUS DISEASES 2016 Week No: 5 L. Dr. Yahia I. Khudair ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, • Unthrifty persistently infectedcalves. General malnutrition. Copper deficiency. Chronic pneumonia • Reprod uctive failure. Common causes of reproductive failure in dairy and beef cattle herds characterized by anestrus, failure to breed, unsatisfactory semen, failure of fertilization, embryonic mortality, fetal resorption, fetal mummification, abortion, stillbirth, and perinatal mortality • Neonatal calf diarrhea. All common causes of acute undifferentiated diarrhea of calves under 30 days of age. • Congenital defects of calves. All inherited defects of the nervous system of calves manifested clinically at birth, and diseases of uncertain etiology characterized by nervous system involvement TREATMENT There is no specific treatment for any of the diseases associated with the BVDV. The prognosis for severe cases of mucosal disease with profuse watery diarrhea and marked oral lesions is unfavorable and slaughter for salvage or euthanasia should be considered. Animals with chronic BVD should be culled and destroyed. CONTROL AND PREVENTION Test and isolate additions to your herd. Make sure your herd is properly vaccinated. Keep in mind that vaccination is not 100% protective. Test for and cull persistently infected heifers. Immediately separate affected and exposed animals from the rest of the herd. Even a well-prepared herd may succumb to BVD when introducing new animals if the right mix of naïve and shedding animals with the right mix of viral types meet. Page 11