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Bovine Viral Diarrhoea Virus (view source)
Revision as of 18:34, 23 August 2010
, 18:34, 23 August 2010→Pathogenesis
==Pathogenesis==
==Pathogenesis==
Initially, BVDV replicates in the nasal mucosa and tonsil to high titres. After spreading to regional lymph nodes, the virus disseminates throughout the body reaching highest concentrations in the tonsil, thymus and ileum. Leucocytes are also infected (Bruschke et al., 1998). BVDV can infect cells of the bone marrow (Spagnuolo et al., 1997), and intestinal mucosa. Lymphoid tissue of the Peyer’s patches and thymus is often depleted.
BVDV infection can result in a range of clinical diseases, from subclinical infections to the highly fatal mucosal disease. While inter-genotype virulence differences are partially responsible for the variations in clinical manifestation, host factors are also important. Immuno-competence or immunotolerance, pregnancy status, gestational age of foetus, passively versus active immunity and levels of environmental stress may all contribute to the severity of disease.
1.2.1 Infection of the Immunocompetent, Non-Pregnant, Seronegative Animal
BVDV is generally considered a mild disease in immunocompetent cattle; it has been estimated that 70% to 90% of BVDV infections occur without clinical signs (Ames, 1986). If closely observed, sub-clinically infected cattle may show a small increase in body temperature, mild leucopaenia, and agalactia (Perdrizet et. al, 1987; Moerman et. al, 1994).
Clinical disease is known as BVD. This tends to affect animals 6-12 months of age with high morbidity, although fatality is uncommon (Baker, 1995). An incubation period of 5-7 days is followed by pyrexia and leucopaenia. Viraemia is apparent from 4-5 days post-infection, and may continue until day 15 (Duffell and Harkness, 1985). BVD no longer seems to present as herd outbreaks of diarrhoea (Brownlie, 1985). Although diarrhoea does sometimes occur, clinical findings more commonly include depression, anorexia, occulo-nasal discharge, decreased milk production and, occasionally, oral lesions (Baker, 1995). A rapid respiratory rate resembling pneumonia may also be observed (Perdrizet et. al, 1987).
Acutely infected non-pregnant animals shed low concentrations of virus compared to persistently infected cattle (Duffell and Harkness, 1985). Animals produce antibodies to BVDV 2 to 4 weeks after infection (Baker, 1995), which persist for life.
“Severe BVD” also exists, seen in the UK in 1992-1993 (Hibberd and Turkington, 1993), and in herd outbreaks between 1993 and 1995 in Ontario (Carman et. al, 1998). Infected animals showed acute onset of diarrhoea, fever and decreased milk production, sometimes proving fatal. Non-cytopathic, type 2 viruses were implicated in these cases, raising the issue of the degree of cross protection afforded by type 1 vaccines. However, severe disease was only seen in cattle where vaccine manufacturers’ instructions had not been followed, implying protection is usually given.
BVDV2 infection may also result in haemorrhagic syndrome (HS), reported in both North America (Perdrizet et. al, 1987; Rebhun et.al, 1989) and Europe. This is characterised by significant thrombocytopaenia, giving rise to bloody diarrhoea, petechial haemorrhages of mucous membranes and epistaxis (Rebhun et. al, 1989). Fever and leucopaenia are also seen.
1.2.2 Infection of the Immunocompetent, Pregnant, Seronegative Animal
Immunocompetent, pregnant cattle show the same responses to BVDV infection as non-pregnant animals. However, BVDV has a high potential to cross the placenta and infect the developing foetus, meaning additional outcomes of infection may occur in the calf. The main factor influencing the virus’s effects on the foetus is the gestational age at the time of transplacental infection.
Infection at the time of insemination may result in reduced conception rates, and that shortly after increases loss of embryos (Carlsson et. al, 1989; McGowan et. al, 1993). Foetal infection in the first trimester (50-100 days) can cause death, although expulsion of the foetus may not occur until several months later.
Figure 1.4: (from Brownlie et al., 2000) A calf stillborn due to transplacental BVDV infection.
Transplacental infection between days 100 and 150 may result in congenital defects. At this stage the immune system is in the final phase of development, and mounts an inappropriate inflammatory response to BVDV to cause these effects (Duffell and Harkness, 1985). Growth defects in organs such as the thymus, and central nervous system pathologies such as cerebellar hypoplasia, often arise (Brownlie, 1985). Calves with cerebellar hypoplasia are ataxic, reluctant to stand and may suffer tremors (Baker, 1995). Infection at this point may also cause visual problems, including blindness and cataracts. Virus may localise to the vascular endothelium, causing vasculitis and associated inflammation, oedema, hypoxia and cellular degeneration (Brownlie, 2000). Weak, stunted calves may also be produced.
Infection in the third trimester trimester (over 180-200 days) elicits a response from the fully-developed immune system, giving rise to normal but seropositive calves.
1.2.3 Persistent Infection- Immunotolerant Animals.
Infection of the foetus with non-cytopathic virus before 120 days gestation may result in the birth of immunotolerant and persistently infected (PI) calves. The immune system, although competent, recognises the antigen as “self” rather than “foreign” and no response is mounted. The calf therefore develops a tolerant state to the virus which persists into neonatal life. Although no antibodies are produced against the original, transplacental-infecting strain, heterologous BVDV strains can elicit a response in PI cattle. Therefore, these may prove seropositive if tested (Bolin, 1985).
While they may appear clinically healthy, PI animals continuously shed large amounts of virus throughout their lives, providing a major source of infectious virus for naïve cattle. (Houe, 1999). PI dams produce PI calves, resulting in PI family lines which maintain the virus in a herd (Baker, 1995). 1-2% of the cattle population are PI (Houe, 1999), rising to 13% in foetal calves.
PI cattle are predisposed to other diseases, and have a reduced survival rate (Houe, 1993) with 50% dying within their first year (Duffell and Harkness, 1985). This increased susceptibility may be due to BVDV-associated immunosupression, considered in section 1.2.5. Animals may be undersized and slow-growing, and persistent infection is the prerequisite for mucosal disease.
1.2.4 Mucosal Disease
Mucosal disease (MD) primarily affects 6-18 month-old cattle and is invariably fatal (Brownlie et. al, 2000). Baker (1995) summarises the characterising symptoms, which last several days to weeks. These include pyrexia, depression and weakness. Anorexia gives emaciation and dehydration. Foul-smelling, sometimes bloody, watery diarrhoea develops 2-3 days after the onset of disease. Animals are often euthanised for humane reasons.
As suggested by the name, lesions develop on mucosal surfaces including the oral mucosa, tongue, external nares and the buccal and nasal cavities (Brownlie, 1985). Coalition of lesions gives larger areas of necrosis (Baker 1995), leading to excessive salivation, lacrimation, and ocular discharge. The coronet and interdigital surface are also affected, causing the animal to become disinclined to walk and eventually recumbent (Brownlie, 1985). Lesions of the abomasum and small intestine are seen on post-mortem examination, and congestion of the large intestine mucosa results in a stripy, thickened appearance (Brownlie, 1985). Figure 1.5 shows examples of tongue and small intestine lesions.
MD occurs when animals persistently infected with noncytopathic BVDV are superinfected with an antigenically similar cytopathic strain. Cytopathic virus arises from the persistent noncytopathic virus by mutation (see 1.1.4), and may then be transmitted to cause MD in animals PI with the same noncytopathic strain. Immunotolerance induced by the noncytopathic strain prevents superinfecting virus being recognised by the immune system; the biotypes are “homologous” to the immunotolerance (Brownlie, 1990). “Heterologous” superinfection with a non-related cytopathic biotype causes an antibody response and mucosal disease does not usually occur.
Figure 1.5: (From Brownlie, 1985) a) Tongue of a calf suffering mucosal disease. Complete loss of the epithelium has occurred at the apex. b) Lesion of the small intestine due to MD. These may appear chronic, and have food adhering to the surface.
1.2.5 Immunosupression in Mixed Infections
BVDV-induced leucopaenia reduces the defences available against invading pathogens, enhancing the pathogenicity of co-infecting organisms. BVDV can therefore be considered an immunosuppressive agent.
BVDV-associated immunosupression has a particularly important role in bovine respiratory disease, with an association between BVDV antibody titre and respiratory disease treatment being demonstrated (Martin and Bohac, 1986). BVDV is the virus most frequently isolated from pneumonic lungs, often found in association with Pasteurella haemolytica (described by Baker, 1995). This pathogen combination causes severe fibrino-purulent bronchopneumonia, with the area of pneumonic lesions increasing by 35-60% compared to that caused by Pasteurella infection alone (Brownlie, 1985). Synergism is also displayed with parainfluenza, bovine rhino-tracheitis and respiratory syncitial viruses.
==Diagnosis==
==Diagnosis==