Epidemiological features and economical importance of bovine virus diarrhoea virus (BVDV) infections

Veterinary Microbiology 64 (1999) 89±107

Epidemiological features and economical importance of bovine virus diarrhoea virus (BVDV) infections Hans Houe* The Royal Veterinary and Agricultural University, BuÈlowsvej 13, Frederiksberg C 1870, Denmark

Abstract Infections with bovine virus diarrhoea virus (BVDV) are widespread throughout the world. Although the prevalence of infection varies among surveys, the infection tends to be endemic in many populations, reaching a maximum level of 1±2% of the cattle being persistently infected (PI) and 60±85% of the cattle being antibody positive. Persistently infected cattle are the main source for transmission of the virus. However, acutely infected cattle as well as other ruminants, either acutely or persistently infected, may transmit the virus. Transmission is most efficient by direct contact. However, as infections have been observed in closed, non-pasturing herds, other transmission routes seem likely to have some practical importance. Differences in BVDV prevalence among regions or introduction of virus in herds previously free of BVDV are often associated with particular epidemiological determinants such as cattle population density, animal trade and pasturing practices. However, on a few occasions there have been no obvious explanations for infection of individual herds. Estimates of economic losses due to BVDV infection vary depending on the immune status of the population and the pathogenicity of the infecting virus strains. Introduction of the infection into a totally susceptible population invariably causes extensive losses until a state of equilibrium is reached. Infection with highly virulent BVDV strains causing severe clinical signs and death after acute infection gives rise to substantial economical losses. At an estimated annual incidence of acute infections of 34%, the total annual losses were estimated as US$ 20 million per million calvings when modeling the losses due to a low-virulent BVDV strain. At the same incidence of infection, the losses due to a high-virulent BVDV strain were estimated as US$ 57 million per million calvings. Low-virulent BVDV infections caused maximum losses at an incidence of 45%, whereas high-virulent BVDV infections caused maximum losses at an incidence of 65%. Thus, cost-benefit analyses of control programs are highly dependent on the risks of new infections under different circumstances and on the strains of the virus involved. # 1999 Elsevier Science B.V. All rights reserved. Keywords: Bovine virus diarrhoea virus; Pestivirus; Epidemiology; Economy; Cattle * Present address: Research Centre for the Management of Animal Production and Health, Foulum, P.O. Box 50, 8830 Tjele, Denmark 0378-1135/99/$ ± see front matter # 1999 Elsevier Science B.V. All rights reserved. PII: S 0 3 7 8 - 1 1 3 5 ( 9 8 ) 0 0 2 6 2 - 4

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1. Introduction The pathogenesis of BVDV infections shows characteristic features not seen in other diseases. The consequences of foetal infection including the relatively long-living PI animals and ensuing development of mucosal disease are unique to BVDV (Brownlie et al., 1984; McClurkin et al., 1984; Bolin et al., 1985). The clinical manifestations can be diverse and losses can be incurred for several years in cattle herds (Roeder and Drew, 1984; Barber et al., 1985; Brownlie, 1985; Taylor et al., 1997a, b). The characteristic features of BVDV pathogenesis are also reflected in the epidemiology of the infection. Thus, the prevalence and spread of infection can be described both for acutely infected and PI animals. In epidemiological studies, the challenging objectives are to describe how the virus spreads between and within cattle herds, to find methods that describe the stage of infection in the herd, particularly identifying PI animals, and to quantify the economic losses of the infection. Many of these questions have direct relevance for decisions regarding a control strategy. The present review will concentrate on epidemiological and economical features of BVDV infection which have relevance to the design of control strategies aimed at eliminating the infection. The occurrence of infection, the risk of herd infection, the sensitivity, specificity, and predictive value of diagnostic methods at the herd level and the economical losses will be reviewed. When describing prevalence and incidence of infection in countries having initiated control programs, mainly results from before or at the beginning of the control program will be included. 2. Prevalence and incidence of infection The prevalence of BVDV infections has been investigated in several cross-sectional studies as reviewed previously (Houe, 1995). Different surveys show considerable variation in the prevalence of PI animals as well as prevalence of antibody positive animals. Several differences in cattle population structure, housing systems and management can account for the variation in prevalence of infection. For example, in the Scandinavian countries, southern regions with high cattle population density and larger herds had higher prevalence of infection than regions located in the northern part where cattle population density is low and herds are smaller in size (Alenius et al., 1986; Houe and Meyling, 1991; Lùken et al., 1991a). In Spain, a positive correlation between seroprevalence and population density of either dairy cows or dairy farms was found (Vega et al., 1997) and in Canada, the number of cases submitted to the diagnostic laboratories reflected those geographic areas with the highest cattle density (Alves et al., 1996a). In housing systems where cattle are kept under close confinement a PI animal can infect more than 90% of other cattle in the herd before it has reached 3±4 months of age (Houe et al., 1993a). A delayed transmission within the herd is seen when cattle are kept in separate buildings or pens (Houe et al., 1995a; Taylor et al., 1997a. With the same incidence rate, the prevalence of infection within an area will be higher if the speed of transmission within the herd (i.e. a determinant for the duration of infection) is slow than if it is fast. Among the management components, the extent of animal trade, use of

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pasture, and the use of vaccination vary considerably among different regions (Houe et al., 1995b). Especially, common pasturing e.g. as widely used in the Alps, represents a risk to previously uninfected herds (Schaller et al., 1996). However, the exact importance of these management parameters is difficult to assess due to a small sample size in most prevalence studies. There is a predominance of studies showing somewhat similar prevalence of approximately 0.5% and 2% PI animals and 60% and 85% antibody positive animals (Harkness et al., 1978; Meyling, 1984; Howard et al., 1986; Edwards et al., 1987; Liess et al., 1987; Reinhardt et al., 1990; Houe and Meyling, 1991; Frey et al., 1996; Braun et al., 1997; Vega et al., 1997). Only a few prevalence surveys have been performed in beef cattle herds. The estimated prevalence of PI animals among a subsample of 5129 feed lot calves in Canada was less than 0.1% (Taylor et al., 1995). A survey of 1755 animals in 119 unvaccinated cow-calf operations in the US revealed an antibody prevalence of 57% (Paisley et al., 1996). In New Zealand, the antibody prevalence among 140 beef cattle was 63% (PereÂz et al., 1994). The annual incidence of risk of infection has been estimated to be 34% at the individual animal level in Denmark (Houe and Meyling, 1991). In a spreadsheet model it could be calculated that the infection caused a maximum level of financial losses at an annual incidence risk of approximately 45% (Houe et al., 1993b). This corresponded to a maximum prevalence of PI animals born of 3.4%. However, considering the high mortality among PI animals (Houe, 1993) the prevalence of PI animals in a population infected with BVDV at its maximum level will be less than 2%. Thus, it seems from a number of surveys that BVDV in many areas has spread in the cattle population to a level close to the maximum possible level. But still, in some areas there seems to be much less infection due to the circumstances mentioned above. The prevalence of herds with current or recent infection shows considerable variation. Studies based on the detection of BVDV antibodies, either in individual animals or in bulk milk, have shown that the prevalence of infected herds is most often in the range of 70% to 100% (Edwards et al., 1987; Reinhardt et al., 1990; Houe and Meyling, 1991; Niskanen et al., 1991; Niskanen, 1993; Braun et al., 1997; Vega et al., 1997). However, in Norway, the prevalence of infected herds was 37% among dairy herds (Waage et al., 1997) and in Finland less than 1% among dairy herds (Laamanen and Veijalainen, 1997), both studies based on antibody detection in bulk milk. Only a few studies have provided indications of the prevalence of herds with PI animals. In Denmark 10 out of 19 herds (53%), in US 3 out of 20 herds (15%), and in Germany 149 out of 329 herds (45%) were found to have PI animals (Houe and Meyling, 1991; Houe et al., 1995a, Frey et al., 1996). Based on bulk tank milk testing of all 16 113 dairy herds in Denmark, 39% of the herds were estimated to have PI animals (Bitsch and Rùnsholt, 1995). At the herd level, a study in Denmark revealed new infections in 8 out of 9 herds examined, corresponding to an annual incidence risk of new infections of 52% (Houe and Palfi, 1993). In Sweden, repeated examination of bulk milk antibody level revealed a significant increase in 5 out of 43 herds with an initial low titer in one study and 7 out of 91 herds in another study, corresponding to an annual incidence of 12% and 8%, respectively (Niskanen, 1993; Niskanen et al., 1995).

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Table 1 shows a serological survey for BVDV antibodies in 10 young stock performed in each of 41 Danish dairy herds 2 years apart. Considering herds with  3 antibody positive animals among 10 young stock as not currently infected and herds with  9 antibody positive animals as currently infected, the study showed that 11 out of 24 herds changed from not currently to currently infected over the course of the 2 year study. This corresponds to an annual incidence risk of 26% (Houe et al., 1997). In the same 2 year period, 7 of 14 herds (50%) changed from currently to not currently infected. Thus, the Table 1 Serological survey for BVDV antibodies in 10 young stock per each of 41 Danish dairy herds in 1992 as compared to 1994 and possible risk factors for recent infection (Additional data on study described by Houe et al., 1997) Herd number

Number of antibody positive among ten young stock 1992

New introductions 1991±1993

Animals on pasture

Minimum distance to other animals on pasture (m)

Other contact with cattle from other herds

1994

Herd category 1: Not currently infected in 1992 and not currently infected in 1994 22 0 1 12 Yes 10 23 2 0 0 Yes 5 41 0 0 0 Yes 300 51 0 0 0 Yes 5 64 1 0 0 Yes 2 73 0 0 0 No b 74 0 0 0 Yes 100 82 0 0 0 Yes 10 83 0 0 18 Yes 10 91 0 1 0 Yes 6 93 0 0 3 Yes 1 103 0 1 0 Yes 300 104 0 0 0 No b

Animal show Housing None None None None None Pasture Fence break out Fence break out Trailer Fence break out None

Herd category 2: Not currently infected in 1992 and not currently infected in 1994 15 1 10 5 Yes 100 24 1 10 0 Yes 10 42 0 10 a a a 44 0 9 7 Yes 3 45 0 10 6 Yes 4 52 0 10 5 Yes 3 55 3 10 0 Yes 100 81 0 10 0 No b 101 0 10 0 Yes 4 102 1 9 100 Yes 1 105 0 10 3 Yes 1

Animal show None None Fence break out Fence break out Fence break out Fence break out None Fence break out None Animal show

Herd category 3: Not currently infected in 1992 and not currently infected in 1994 14 10 10 30 Yes 400 54 10 10 0 Yes 50 63 10 10 37 Yes 4 71 10 9 30 No b 72 9 10 13 Yes 2000 85 9 10 2 No b 94 8 10 60 Yes 4

None None None None Fence break out None None

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Table 1 (Continued ) Herd number

Number of antibody positive among ten young stock 1992

New introductions 1991±1993

Animals on pasture

Minimum distance to other animals on pasture (m)

Other contact with cattle from other herds

1994

Herd category 4: Not currently infected in 1992 and not currently infected in 1994 11 9 3 0 Yes 3 12 10 0 0 Yes 200 13 9 0 a Yes 10 21 10 0 17 Yes 3 43 10 0 17 Yes 4 53 10 1 30 Yes 2 84 9 0 2 Yes 50

Fence break out None None None None Fence break out None

No category 61 10 92 9 95 10

None Fence break out None

7 4 4

0 60 27

Yes Yes Yes

1 1 1

a

Not answered in questionnaire. No distance, animals not pastured.

b

infection seemed to have been endemic with a high prevalence in the area, but with a frequent change in infection status for individual herds. Based on positive herd submissions, studies on outbreaks of highly virulent BVDV strains in Canada have shown that the infection seemed to have occurred in epidemic rather than endemic form. Thus, in Ontario the number of positive herd submissions to veterinary laboratories increased significantly from approximately 10 positive cases per 500 herd submissions in 1992 to 50 positive cases per 500 herd submissions in 1993. Thereafter the rate leveled off at about 20 positive cases per 500 herd submissions (Alves et al., 1996a, b). BVDV with high virulence often belong to the genotype 2, however, both genotypes 1 and 2 contain highly virulent strains (Bolin and Ridpath, 1996). In most countries, cattle are primarily infected with genotype 1, but in North America, genotype 2 has become common (Carman et al., 1996; Drake et al., 1996; Paton et al., 1996; Sockett et al., 1996; and chapter on antigenic diversity in this issue). The distribution of highly virulent strains as compared to lowly virulent BVDV strains needs further epidemiological study as it has important consequences for transmission and for the financial consequences of infection as discussed later. 3. Transmission of virus PI animals are the main source of virus transmission as they continuously shed large amounts of virus in the environment (Coria and McClurkin, 1978; Straver et al., 1983; Brock et al., 1991). Virus is excreted in smaller amounts from acutely infected animals and for only a few days during the acute infection (Brownlie et al., 1987). Transmission between small ruminants and cattle, both ways, has been demonstrated (Carlsson, 1991;

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Lùken et al., 1991b; Carlsson and BelaÂk, 1994; Paton et al., 1995) and BVDV has been isolated from many other captive and free-living ruminants which are considered a potential source of virus. The detection of a higher prevalence of antibody positive reindeer than cattle and sheep in northern Norway suggests a reservoir among free-living ruminants (Lùken, 1995). BVDV has also been isolated from pigs (Terpstra and Wensvoort, 1988); but their importance in transmission is unclear. Although the prevalence among pigs has been related to contact with cattle (Lùken, 1995), BVDV infection in pigs with no indication of virus transmission from cattle has also been described (Frey et al., 1995). There are several ways by which BVDV can be transmitted from infected to susceptible animals. Direct contact with a PI animal is the most efficient mode of transmission of the virus under natural circumstances (Cook et al., 1990; TraÊveÂn et al., 1991; McGowan et al., 1993; Niskanen et al., 1996). One hour of direct contact allowing nose-to-nose contact was sufficient for transmission to occur (TraÊveÂn et al., 1991). Also direct contact with acutely infected animals can transmit the virus, although less efficiently (Meyling et al., 1990). For example, acute infection among 12 heifers induced by artificial insemination (AI) with infected semen did not spread the infection to four susceptible animals tied in close contact (Meyling and Jensen, 1988). None of 14 calves seroconverted after 2 days in close contact with acutely infected calves, including noseto-nose contact (Niskanen et al., 1996). Bovine virus diarrhoea virus is excreted in semen in both acutely infected and PI bulls. Virus titers of 107 TCID50/ml have been found in semen from PI bulls (Paton et al., 1989), whereas the virus titers in semen from acutely infected bulls reportedly ranged from 5 to 75 TCID50/ml (Kirkland et al., 1991). Twelve antibody negative heifers all seroconverted after artificial insemination with semen from a PI bull (Meyling and Jensen, 1988). For comparison, only 3 out of 60 antibody negative heifers inseminated with semen from an acutely infected bull seroconverted (Kirkland et al., 1997). Infected semen from PI bulls can be avoided by testing bulls twice for virus in blood before entering the AI centres. In addition, bulls should undergo a quarantine period before entering an AI center in order to overcome the acute phase of the infection and no longer to shed virus. However, an acutely infected bull may still pose a threat as it can escape both virus and antibody detection tests, enter the quarantine facilities and initiate an acute infection among other bulls which may still shed the virus when released from quarantine. In addition, virus may continue to be shed in semen after the end of the viraemia (Kirkland et al., 1991) and persistently shedding of BVDV in semen has been observed in one bull in the absence of viraemia (Voges, 1997). Therefore, regular testing of bulls at AI centers for seroconversions and for virus in semen may also be essential. Transmission via embryo transfer is possible, but can be avoided using recommended washing procedures, even when embryos are transferred from PI donor cows (Wentink et al., 1991a; Bak et al., 1992; Brock et al., 1997). However, the recommended washing procedures were ineffective for removal of BVDV from an in vitro fertilization system (Bielanski and Jordan, 1996). Attention should be paid to the use of foetal calf serum used for embryo transfer as it may be contaminated with BVDV. Several ways of indirect, vehicle or vector transmission of BVDV have been demonstrated, i.e. reusing needles and nose tongs (Gunn, 1993), rectal gloves (Lang-Ree

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et al., 1994) or by using live or contaminated vaccines (Liess et al., 1984; Lùken et al., 1991b). Transmission can also occur through blood feeding flies (Tarry et al., 1991). However, many of the experimental transmission studies have used a shorter time period between contact with the infected animal and the susceptible animal than would occur between two herd visits, and thus their practical importance requires clarification. In general, pestiviruses are relatively easily inactivated, and their infectivity outside the host is of short duration (Hafez and Liess, 1972; Duffel and Harkness, 1985; Liess, 1990). The possibility of airborne transmission has not been proven and remains controversial, but transmission by air is considered possible over several meters by some authors (Bitsch and Rùnsholt, 1995). The infectious dose of virus is highly dependent upon the route of transmission. One study showed that the highest dilutions of serum from a PI animal with a virus titer of undiluted serum of 104.3 TCID at which seroconversion occurred were: (1) undiluted by the conjunctival route (0.5 ml), (2) 10ÿ1 by the intranasal route (2 ml), and (3) 10ÿ5 by the subcutaneous route (2 ml) (Cook et al., 1990). 3.1. Transmission within herds The rate of BVDV transmission within a herd depends on whether the virus is introduced by a PI animal, or by some other means starting an acute infection without the initial presence of PI animals. The finding that PI animals often occur in two separate age groups probably indicates that there were two episodes of acute infection among the cows. This means that the infection is often introduced by means other than PI animals, and that the following initial acute infection is of short duration (a few weeks) and only includes a small percent of the herd before the transmission ceases (Houe, 1992a). Other field studies have shown somewhat different results concerning the acute infection. In two studies, the virus circulated for 2±2.5 years although there were no PI animals present and no direct contact with PI cattle was found (Barber and Nettleton, 1993; Moerman et al., 1993). However, the exact nature of the slow spread of virus requires further clarification. Thus, it could be anticipated that the apparent slow circulation was in fact multiple introductions of new virus at different times (as suggested by Barber and Nettleton, 1993) instead of a single ongoing transmission from acutely infected animals. The virulence of the virus may influence the rate and extent of virus transmission. Several cases of acute BVDV with severe disease within a few weeks have been reported (David et al., 1994). In another study of outbreaks of acute BVD infection in ten herds, the virus spread to numerous animals, but it was more slowly progressing, and the mean duration of outbreaks was 13 weeks with a range of 4 to 32 weeks (Tremblay et al., 1996). Should a more efficient spread of virus be a true phenomenon when animals are acutely infected by a virulent BVDV strain, it may not only be a characteristic of the virus itself but also an effect of the clinical signs such as coughing which may increase the amount of virus excreted. When PI animals are born, secondary transmission to the remaining susceptible animals occurs rapidly (Houe, 1992a). As mentioned previously, the PI animals in one

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study had infected more than 90% of cattle in the herd before 3±4 months of age (Houe et al., 1993a). This was also seen in the study by Moerman et al. (1993), where all susceptible cattle that came into contact with a PI animal became seropositive within 3 months. In another study, seronegative animals seroconverted within 5 months after the introduction of a PI animal. At short distances, the animals had seroconverted within 2 months, whereas at longer distances the time of seroconversion was more undefined (Wentink et al., 1991b). In herds where animals are housed and pastured in segregated groups, the transmission from PI animals may be prevented until the PI animals come in closer contact with susceptible animals (Houe et al., 1995a; Taylor et al., 1997a). It is unclear if the spread of virus from PI animals is primarily from the PI animal itself, or mostly from secondary acute infections. But, considering the limited spread from acutely infected animals, it is most likely that the virus is most often transmitted from the PI animals themselves. If that is the case, transmission would most likely be through the air as it would be improbable that a PI animal would have direct or indirect contact with all remaining animals, although some transmission could occur with feed, manure, buckets or other tools used by the caretaker. However, the question of airborne transmission needs further investigation. Although there are some discrepancies about the rate by which acute infection spreads in a herd, it usually has little practical importance. In most cases, a cow in early pregnancy will sooner or later become infected, and the ensuing PI calf will reinforce the transmission with the eventual infection of the whole herd. 3.2. Transmission between herds Bovine virus diarrhoea virus (BVDV) is most obviously introduced into a susceptible herd by purchase of PI animals or pregnant animals carrying a PI foetus. Thus, if the prevalence of PI animals is 2% (including animals carrying a PI foetus), the risk (P) of introducing PI animals when buying from random sources without testing is {1ÿ(the probability of buying a non-PI animal)n}, where n is the number of animals purchased i.e. P ˆ 1±0.98n. Thus, buying 20 animals involves a calculated risk of 1±0.9820 ˆ 33%. However, it has been shown that the infection is introduced much more frequently than can be explained from the risk of purchasing PI animals and new infections have been seen in herds without the purchase of any animal in recent years (Houe and Palfi, 1993). Assuming an annual risk of infection of 30% in a population where 50% of the animals are antibody positive, and again assuming that an acutely infected animal is spreading virus for 10 days (2.7% of the year), then the average risk of buying an acutely infected animal will be on average: 0.3  0.5  0.027 ˆ 0.4%. Like the risk of introducing PI animals as calculated above, the risk of introduction of acutely infected animals from purchasing a group of 20 animals will be: 1±0.99620 ˆ 8%. However, as previously indicated, only some of the acutely infected animals will transmit the virus. Although these calculations are only rough estimates, purchase of animals without any testing or quarantine is both practically and theoretically demonstrated to be a very important means of introducing BVDV infections. Contact with cattle from other herds such as pasturing at close distance, fence break out, animal shows etc. may also be important for transmission of BVDV. Table 1 presents

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a repeated serological survey of 41 Danish dairy herds including some possible risk factors for new infection. In that study, purchase of animals was a significant risk factor for a high number of antibody positive animals (P ˆ 0.05). Pasturing of cattle at a distance of less than 5 m to cattle from other herds or contact with cattle from other herds by other means was found to be moderately associated with the number of antibody positive animals (P ˆ 0.085) (Houe et al., 1997). In herds with BVDV infections there almost always seem to be some contact that can explain new infections. Among the 11 herds in Category 2 (Table 1) that changed from lowly to highly infected, some contact with cattle from other herds was documented in most cases. However, Herd 81 had no possible contact with other cattle, but one lamb had been brought into the herd in 1992. The lamb was never tested, but it could have been the source of virus. A closer investigation of reinfections in a larger number of herds is needed to clarify the importance of cattle contact compared with other routes including indirect contact through people and their equipment for transmission of BVDV. The epidemic of acute BVD in Ontario in 1993 indicates that highly virulent strains can spread rapidly between herds (Alves et al., 1996a, b). However, whether the highly virulent strains spreads more rapidly than low virulent strains or they just seem to spread more rapidly because of earlier detection of disease symptoms, needs to be clarified. Also the importance of co-infections needs to be clarified. Thus, an increase of abortions due to Neospora sp was also seen (Alves et al., 1996a, b). 4. Sensitivity, specificity and predictive value for diagnosis on the herd level In countries not using vaccination, the immense transmission of BVDV from PI animals can be used to indirectly identify herds with such animals, either by serological examination of a few young stock (Houe, 1992b, 1994) or by determination of antibody levels in bulk milk (Niskanen, 1993; Houe, 1994; Bitsch and Rùnsholt, 1995). The use and interpretation of these antibody detection methods are closely linked to the epidemiology of BVDV. Five phases in the infection cycle can be considered (Houe, 1995): Phase A. Recently infected herd without the presence of PI animals. Often only a small percentage of the herd will be seropositive. Phase B. Infected herd with PI animals younger than 3±4 months old. Most animals are undergoing acute infection at varying speed depending on the housing of the animals. Phase C. Infected herd with PI animals older than 3±4 months old. Usually more than 90% of the animals are seropositive. Phase D. Previously infected herd where PI animals have recently been removed. Young stock are becoming antibody negative as they loose colostral antibodies at 6±8 months of age. Cows remain seropositive. Phase E. Previously infected herd where PI animals have been removed several years ago. All young stock (except some colostral antibody positive calves) and many of the younger cows are antibody negative. Eventually the herd becomes completely naive. Using a small sample of young stock to predict presence or absence of PI animals on a farm is most useful when either almost all the young stock are antibody positive or almost

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Table 2 Evaluation of testing a small screening sample of young stock for antibodies against BVDV in order to predict presence or absence of PI animals (at a herd prevalence of 58%) Presence of PI animals

Total

Yes

No

Spot test positive Spot test negative

14 1

0 11

14 12

Total

15

11

26

Sensitivity (SE), 14/15 ˆ 0.93 Specificity (SP), 11/11 ˆ 1.00 Positive predictive value (PPV), 14/14 ˆ 1.00 Negative predictive value (NPV), 11/12 ˆ 0.92

all are antibody negative i.e. phase C versus phase D and E. In contrast, recently infected herds and herds with young PI animals (phase A and B) will result in a less predictable number of antibody positive animals in the screening sample. In two studies, a total herd blood test was performed in 26 herds and with an accuracy close to one, 25 of the herds were correctly classified according to presence of PI animals using spot test sampling (Houe, 1992b, 1994). The spot test analyses in these studies as evaluated in a 2  2 table (Table 2) shows high values of sensitivity (SE) and specificity (SP) and also, at the prevalence levels in these studies, high values of positive predictive value (PPV) and negative predictive value (NPV). However, herds with young PI animals may be misclassified as not having PI animals and herds from which PI animals have been recently removed may be misclassified as having PI animals. These problems of misclassification can be avoided by repeating the spot test analyses 6 months later. Measurement of antibody level in bulk milk will give an indication of the prevalence of seropositive cows in the herd. However, after removal of PI animals from a herd, cows will usually remain antibody positive for the rest of their lives and the antibody level will decline slowly mostly depending on replacement by antibody negative cows. Fig. 1 shows the decline in antibody reaction in ten herds after removal of PI animals. Thus, as both phase C and D have a high prevalence of antibody positive cows, the test is not useful for distinguishing these two categories. On the other hand, the test is very applicable for surveillance of herds with low prevalence of antibody positive animals among cows. Especially, detection of antibody levels in bulk milk can distinguish the totally naive herds from chronically or recently infected herds. However, in infected areas there are very few totally naive herds, and the use of antibody level in bulk milk for surveillance for the presence of any seropositives is therefore more useful in the later phases of an eradication program or when the infection has been totally eradicated. In Denmark, the antibody levels in bulk tank milk, as measured by a blocking ELISA, were compared with the results of a spot test examination of three young stock for antibodies in 352 Danish dairy herds (Bitsch and Rùnsholt, 1995, Table 3). Using the spot test analyses as the standard, the sensitivity, specificity and predictive values of antibody level in bulk milk were calculated. As the antibody level in bulk milk is a quantitative measure, the calculations can be made at different definitions of a positive test result (Table 4). Table 4 shows that the sensitivity is generally high, i.e. the test will find most

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Fig. 1. Antibody reaction in bulk milk measured by blocking ELISA in ten herds at various times after removal of PI animals from the herd

Table 3 Correlation between the BVDV herd infection status measured by antibody status among a spot sample of young stock and BVDV antibody reaction in bulk milk measured by a blocking ELISA Antibody level in bulk milk (blocking percentage)

Spot test analyses

Total

Positive

Negative

0±50 51±60 61±70 71±80 >80

0 0 3 14 75

161 14 18 35 32

161 14 21 49 107

Total

92

260

352

Data from: Bitsch and Rùnsholt, 1995. (Control of bovine viral diarrhea virus infection without vaccines. Vet. Clin. North Am. Food Anim. Pract., 11, 627±640, with permission).

Table 4 Sensitivity, specificity and predictive values of antibody level in bulk milk at different cut off values as a measure to predict presence or absence of PI animals (at an estimated herd prevalence of 26%) Cut-off value (blocking percentage)

Sensitivity Specificity Positive predictive value Negative predictive value

50

60

70

80

1.00 0.62 0.48 1.00

1.00 0.67 0.52 1.00

0.97 0.74 0.57 0.98

0.82 0.88 0.70 0.93

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herds with PI animals. However as expected, the PPV is very low because many herds without PI animals still have many antibody positive cows, high antibody level in bulk milk, and thus are classified as having PI animals. The best parameter appears to be the NPV, meaning that herds with low level of antibodies truly are free of PI animals. Still, a herd can have been recently infected and PI animals can be forthcoming. Therefore, the antibody level in bulk milk will only suffice to declare a herd as BVDV free if two subsequent bulk milk samples obtained several months apart have had a reaction below 50 per cent. 5. Economic aspects The losses due to various forms of BVDV infection include reduced milk production, reduced conception rate, respiratory disorders, other diseases, and even death among animals acquiring acute infection, and abortions, congenital defects, and growth retardation after foetal infection. In addition, foetal infection leads to PI calves which often are small and unthrifty, have increased susceptibility to other diseases, and may eventually die from mucosal disease. The exact quantification of the clinical and pathological damages after infection in a population is difficult because most descriptions in the literature are based on selected clinical outbreaks and are thus not representative of the broad spectrum of the disease. Only a few studies have examined the effect of BVDV in herds not selected on the basis of clinical outbreaks. Reviews of the clinical and pathological effects of BVDV infections and quantification of some of the damages have recently been published (Baker, 1995; Bielefeldt-Ohmann, 1995; Houe, 1995). An epidemiological study examining the effect of BVDV infection on the general health of cattle herds showed BVDV associated with increased risk of clinical mastitis, retained placenta, oestrus-stimulating treatments and longer calving intervals (Niskanen et al., 1995). Calculations of the economic losses are complex, and the losses in a herd from an outbreak vary according to the initial herd immunity, pregnancy status of the cows at the time of the infection, and the virulence of the infecting virus strain. Accordingly, calculations of economic losses in individual herd outbreaks may vary from a few hundred to several thousand dollars (Duffel et al., 1986; Wentink and Dijkhuizen, 1990; Houe et al., 1993b). Estimates of economic losses from infection with highly virulent strains have ranged from US$ 40 000 to 100 000 per herd (Carman et al., 1994 cf. Alves et al., 1996a, b). Although some outbreaks can be devastating for the individual producer, calculations of the national losses are more relevant as a basis for deciding between control and eradication within a particular country. However, due to the variation among losses in individual herds, these calculations can only be approximated. The losses at the population level have been estimated in the range of US$ 10±40 million per million calvings (Bennet and Done, 1986; Harkness, 1987; Spedding et al., 1987; Houe et al., 1993a, b; Houe, 1995). In Denmark, with an estimated annual incidence of acute infections of 34%, the total annual national losses in 1992 were estimated to be US$ 20 million (Houe et al., 1993a, b). The maximum losses were seen at an incidence of 45% (Fig. 2). At higher incidence

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Fig. 2. Economic losses among dairy cattle per million calvings due to BVDV infection at different annual incidence risks. Low-virulent BVDV strain. From Houe et al., 1993b. A computerised spread sheet model for calculating total annual national losses due to bovine virus diarrhoea virus (BVDV) infection in dairy herds and sensitivity analysis of selected parameters. (Proceedings of the 2nd Symposium on ruminant pestiviruses. 1±3 October 1992, pp. 179±184), with permission.

risk, the losses were lower because many animals would be immune before their first pregnancy. The calculated losses were based on experiences from BVDV infections in Danish dairy herds and from the literature at that time. However, several recent publications have described much more severe outbreaks from more virulent strains such

Fig. 3. Economic losses among dairy cattle per million calvings due to BVDV infection at different annual incidence risks. High-virulent BVDV strain.

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as those belonging to genotype two. Fig. 3 shows a re-run of the previous model (Houe, 1993), but using estimated losses that can occur from such highly virulent strains. The estimated losses are based on recent descriptions of such outbreaks (Hibberd et al., 1993; Carman et al., 1994; David et al., 1994; Drake et al., 1994; Tremblay et al., 1996). The following changes were made in the model: risk of respiratory disease following acute infection was increased from 2±3% to 5%, risk of other diseases following acute infection was increased from 1% to 10%, risk of reduced milk production following acute infection were increased from 10% to 20%, and risk of death following acute infection was increased from 0.25% to 10%. The abortion risk following foetal infection was doubled compared to the previous model, i.e. depending on the gestational stage from 5±20% to 10±40%. Because of the higher mortality, the culling rate was reduced to keep a stable population. Otherwise, the model was the same as described earlier (Houe et al., 1993a, b) with the same monetary values as in 1992. Under these circumstances, the total annual national losses in Denmark at an annual incidence risk of 34% were estimated at US$ 57 million per million calvings or almost 3 times more than previously calculated. Another important difference is that the maximum losses under the new circumstance is now seen at an incidence risk of 65% instead of 45% (Fig. 3). Thus, the value of deliberately exposing animals to PI animals in order to immunize the population would be much smaller if all BVDV infections occurred with a highly virulent strain. The economical importance of a disease and the outcome of various control strategies should be evaluated in terms of the costs and benefits to society, i.e. social cost benefit analysis. Few such attempts have been made concerning BVDV (Bennet and Done, 1986; Spedding et al., 1987). Also, there is a need for sensitivity analyses of such attempts due to the many existing uncertainties, especially those regarding the distribution of strains with different virulence. There is still only moderate information regarding the number of reinfections that might occur, which is a crucial factor in order to perform cost benefit analyses. In Norway, 108 out of 3030 (3.6%) previously infected herds but released from restrictions during 1989±1996 have later been renotified (Waage et al., 1997) and in Sweden the herd level annual incidence risk was approximately 3% from 1993 to 1995 (Alenius et al., 1997). The eradication and control expenses in Denmark over a 3-yearperiod have been estimated to be US$ 27 million (Bitsch and Rùnsholt, 1995). Thereafter, there will only be minor costs to the continued national surveillance. Compared to the annual losses of infection of US$ 20 million, there would be a very high benefit to eradication under the assumption that reinfections would be rare.

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