Responses to diagnostic tests for bovine tuberculosis in dairy and non-dairy cattle naturally exposed to Mycobacterium bovis in Great Britain.

Field surveillance of British cattle using the single intradermal comparative cervical tuberculin (SICCT) test shows a higher incidence rate of bovine tuberculosis (bTB) in dairy compared to beef herds, but a lower probability of post-mortem examination confirmed (PMC) Mycobacterium bovis infection in dairy herds. A cross-sectional study was conducted to compare animal level differences in bTB detection between dairy and non-dairy cattle in Great Britain. During the period from 2002 to 2005, 200 (41% dairy) reactors in the SICCT test (standard interpretation) were randomly selected, and 200 in-contact cattle (43% dairy) were purposively selected from bTB-infected herds. Interferon (IFN)-γ responses in blood to bovine and avian purified protein derivative (PPD), and early secretory antigen target 6 kDa and culture filtrate protein 10 (ESAT-6/CFP10), were measured. The post-mortem examination included gross pathological examination, mycobacterial culture and histopathology. The proportions of cattle positive to ESAT6/CFP10 were 26% (95% confidence interval, CI, 15-39%) in dairy reactors and 62% (95% CI 51-72%) in non-dairy reactors (P <0.001). PMC risk was 34% (95% CI 24-45%) in dairy reactors and 69% (95% CI 60-78%) in non-dairy reactors (P <0.001). The odds ratio for PMC risk in dairy reactors compared to non-dairy reactors, after controlling for bTB prevalence, herd size and SICCT test response, was 0.27 (95% CI 0.14-0.53; P <0.001). In surveillance data, adjusted animal level PMC risks were lower for dairy reactors than for beef reactors aged >2 years (P <0.001).

A review of risk factors for bovine tuberculosis infection in cattle in the UK and Ireland.

Bovine tuberculosis (bTB) is an important disease of cattle caused by infection with Mycobacterium bovis, a pathogen that may be extremely difficult to eradicate in the presence of a true wildlife reservoir. Our objective was to identify and review relevant literature and provide a succinct summary of current knowledge of risk factors for transmission of infection of cattle. Search strings were developed to identify publications from electronic databases to February 2015. Abstracts of 4255 papers identified were reviewed by three reviewers to determine whether the entire article was likely to contain relevant information. Risk factors could be broadly grouped as follows: animal (including nutrition and genetics), herd (including bTB and testing history), environment, wildlife and social factors. Many risk factors are inter-related and study designs often do not enable differentiation between cause and consequence of infection. Despite differences in study design and location, some risk factors are consistently identified, e.g. herd size, bTB history, presence of infected wildlife, whereas the evidence for others is less consistent and coherent, e.g. nutrition, local cattle movements. We have identified knowledge gaps where further research may result in an improved understanding of bTB transmission dynamics. The application of targeted, multifactorial disease control regimens that address a range of risk factors simultaneously is likely to be a key to effective, evidence-informed control strategies.

Development of risk-based trading farm scoring system to assist with the control of bovine tuberculosis in cattle in England and Wales.

Identifying and ranking cattle herds with a higher risk of being or becoming infected on known risk factors can help target farm biosecurity, surveillance schemes and reduce spread through animal trading. This paper describes a quantitative approach to develop risk scores, based on the probability of infection in a herd with bovine tuberculosis (bTB), to be used in a risk-based trading (RBT) scheme in England and Wales. To produce a practical scoring system the risk factors included need to be simple and quick to understand, sufficiently informative and derived from centralised national databases to enable verification and assess compliance. A logistic regression identified herd history of bTB, local bTB prevalence, herd size and movements of animals onto farms in batches from high risk areas as being significantly associated with the probability of bTB infection on farm. Risk factors were assigned points using the estimated odds ratios to weight them. The farm risk score was defined as the sum of these individual points yielding a range from 1 to 5 and was calculated for each cattle farm that was trading animals in England and Wales at the start of a year. Within 12 months, of those farms tested, 30.3% of score 5 farms had a breakdown (sensitivity). Of farms scoring 1-4 only 5.4% incurred a breakdown (1-specificity). The use of this risk scoring system within RBT has the potential to reduce infected cattle movements; however, there are cost implications in ensuring that the information underpinning any system is accurate and up to date.

Assessing the impact of a cattle risk-based trading scheme on the movement of bovine tuberculosis infected animals in England and Wales.

The adoption of bovine tuberculosis (bTB) risk-based trading (RBT) schemes has the potential to reduce the risk of bTB spread. However, any scheme will have cost implications that need to be balanced against its likely success in reducing bTB. This paper describes the first stochastic quantitative model assessing the impact of the implementation of a cattle risk-based trading scheme to inform policy makers and contribute to cost-benefit analyses. A risk assessment for England and Wales was developed to estimate the number of infected cattle traded using historic movement data recorded between July 2010 and June 2011. Three scenarios were implemented: cattle traded with no RBT scheme in place, voluntary provision of the score and a compulsory, statutory scheme applying a bTB risk score to each farm. For each scenario, changes in trade were estimated due to provision of the risk score to potential purchasers. An estimated mean of 3981 bTB infected animals were sold to purchasers with no RBT scheme in place in one year, with 90% confidence the true value was between 2775 and 5288. This result is dependent on the estimated between herd prevalence used in the risk assessment which is uncertain. With the voluntary provision of the risk score by farmers, on average, 17% of movements was affected (purchaser did not wish to buy once the risk score was available), with a reduction of 23% in infected animals being purchased initially. The compulsory provision of the risk score in a statutory scheme resulted in an estimated mean change to 26% of movements, with a reduction of 37% in infected animals being purchased initially, increasing to a 53% reduction in infected movements from higher risk sellers (score 4 and 5). The estimated mean reduction in infected animals being purchased could be improved to 45% given a 10% reduction in risky purchase behaviour by farmers which may be achieved through education programmes, or to an estimated mean of 49% if a rule was implemented preventing farmers from the purchase of animals of higher risk than their own herd. Given voluntary trials currently taking place of a trading scheme, recommendations for future work include the monitoring of initial uptake and changes in the purchase patterns of farmers. Such data could be used to update the risk assessment to reduce uncertainty associated with model estimates.

Exploration of the power of routine surveillance data to assess the impacts of industry-led badger culling on bovine tuberculosis incidence in cattle herds.

In the UK, badgers (Meles meles) are a well-known reservoir of infection, and there has been lively debate about whether badger culling should play a role within the British Government's strategy to control and eventually eradicate tuberculosis (TB) in cattle. The key source of information on the potential for badger culling to reduce cattle TB in high-cattle-TB-incidence areas remains the Randomised Badger Culling Trial (RBCT). In late 2013, two pilot areas were subjected to industry-led badger culls. These culls differed importantly from RBCT culling in that free-ranging as well as cage-trapped badgers were shot, and culling took place over a longer time period. Their impacts will be harder to evaluate because culling was not randomised between comparable areas for subsequent comparisons of culling versus no culling. However, the authors present calculations that explore the power of routine surveillance data to assess the impacts of industry-led badger culling on cattle TB incidence. The rollout of industry-led culling as a component of a national cattle TB control policy would be controversial. The best possible estimates of the effects of such culling on confirmed cattle TB incidence should be made available to inform all stakeholders and policy-makers.

Specificity of the comparative skin test for bovine tuberculosis in Great Britain.

A novel method for estimating specificity of the Single Intradermal Comparative Cervical Tuberculin (SICCT) test for bovine tuberculosis (bTB) using surveillance tests results is reported. The specificity of the SICCT test at three cut-offs was estimated from the dates, locations and skinfold measurements of all routine tests carried out in Officially TB Free (OTF) cattle herds in Great Britain (GB) between 2002 and 2008, according to their separation (by distance and time) from known infected (OTF-withdrawn) herds. The proportion of animals that tested positive was constant (P>0.20) when the distance between tested herds and nearest infected herd exceeded 8 km. For standard cut-off, calculated specificity was 99.98 per cent (95 per cent confidence interval ±0.004 per cent), equating to one false positive result per 5000 uninfected animals tested. For severe cut-off it was 99.91 per cent (±0.013 per cent) and for ultrasevere cut-off (selecting all reactors and inconclusive reactors) it was 99.87 per cent (±0.017 per cent). The estimated positive predictive value of the test averaged 91 per cent and varied by regional prevalence. This study provides further evidence of the high specificity of the SICCT test under GB conditions, suggests that over 90 per cent of cattle currently culled using this test in GB were infected, and endorses slaughter of at least these cattle for bTB control.

Bovine TB infection status in cattle in Great Britain in 2013.

This report, provided by the APHA, summarises the infection status of bovine TB in cattle in Great Britain from January 1 to December 31, 2013 and describes some of the temporal trends observed over a longer period. It updates the previous annual summary for 2012, also published in Veterinary Record (VR, June 14, 2014, vol 174, pp 600-604).

Bovine TB infection status in cattle in Great Britain in 2012.

This report, provided by the AHVLA, summarises the infection status of bovine tuberculosis (TB) in cattle in Great Britain from January 1 to December 31, 2012 and describes some of the temporal trends observed over a longer period. The AHVLA intends to produce similar reports for future years to provide a concise summary of how the situation is developing.

Impact of Schmallenberg virus on British sheep farms during the 2011/2012 lambing season.

British sheep farmers were invited to complete a questionnaire about the impact of Schmallenberg virus (SBV) on animal health, welfare and their own emotional wellbeing during the 2011-2012 lambing season, through Defra and Farming Industry websites, letters to farmers who had requested SBV laboratory tests and advertisement at Sheep 2012. The 494 responders included SBV confirmed (positive by RT-PCR) (n=76), SBV suspected by farmer (n=140) or SBV not suspected (n=278). Percentage of barren ewes was similar across SBV groups, however, lamb and ewe losses were higher on responder farms where SBV was confirmed or suspected. The median percentages of all lambs born (and lambs born deformed ) that died within one week of birth was 10.4 per cent (5.5 per cent), 7.0 per cent (2.9 per cent) and 5.3 per cent (0 per cent), respectively, on SBV confirmed, suspected and not suspected farms (P<0.001). Eight to 16 per cent of SBV confirmed or suspected farms reported lamb mortality of ≥40 per cent. Farmer perceived impact was greater where SBV was confirmed or suspected (P<0.001): 25 per cent reported a high impact on emotional wellbeing (4 per cent of SBV not suspected), 13 per cent reported a high impact on flock welfare and financial performance and 6 per cent were less likely to farm sheep next year because of SBV (<2 per cent in SBV not suspected). Overall, SBV impact has been large relative to reported sheep loss.

Mycobacterium bovis infections in domesticated non-bovine mammalian species. Part 1: Review of epidemiology and laboratory submissions in Great Britain 2004-2010.

Mycobacterium bovis, the causative agent of bovine tuberculosis (bTB), can infect a broad range of mammalian species in addition to domestic and feral cattle and badgers. Since legislation introduced in 2006 in Great Britain requires animal keepers, meat inspectors and veterinarians to notify the authorities of suspect bTB lesions or the isolation of M. bovis in any mammal excluding humans, the organism has been increasingly identified in domestic species other than cattle. Although in most cases 'spill-over' hosts, these remain a potential source of infection for cattle, wildlife, and possibly humans. In this first part of a two-part review of M. bovis infections in non-bovine domestic species, current knowledge of the epidemiology of such infections is presented along with novel data relating to diagnostic submissions for mycobacterial culture between 2004 and 2010. Over this period M. bovis infection was identified in 116 cats, 7 dogs, 34 llamas, 133 alpacas, 35 goats, 24 sheep and 85 pigs and wild boar. The risk that such infections pose to the control of bTB, and as zoonoses, is discussed. In part two, the options available to diagnose bTB in these species, as well as the challenges posed to disease detection and control will be discussed in depth.

Mycobacterium bovis infections in domesticated non-bovine mammalian species. Part 2: A review of diagnostic methods.

Despite the large host range of Mycobacterium bovis, ante-mortem diagnostic tests for the infection mostly lack sensitivity/specificity and/or remain unvalidated in non-bovine species. The epidemiology and importance of M. bovis infection in these species are discussed in the first part of this two-part review. This second part focuses on the diagnostic options available to identify infected species such as sheep, goats, dogs, cats, and camelids, and highlights the significant challenges posed, both in establishing estimates of disease prevalence and in controlling infections in these species, in the absence of fully validated tests.

Factors associated with bovine tuberculosis confirmation rates in suspect lesions found in cattle at routine slaughter in Great Britain, 2003-2008.

Bovine tuberculosis (bTB) is one of the most complex and intractable animal health problems facing the British cattle industry today. The inspection of carcasses from cattle sent to slaughter is part of routine surveillance for bTB in Great Britain (GB). Tissue with suspect lesions from cattle from herds previously considered uninfected with bTB is sent to the Animal Health and Veterinary Laboratories Agency (AHVLA) for culture and histopathological examination for Mycobacterium bovis infection. In this study, risk factors for confirmation of infection in suspect bTB lesions found at routine slaughter of cattle from officially bTB-free (OTF) herds in GB were investigated. The study sample included the first record of a suspect lesion in a bovine from any OTF herd identified during post-mortem inspection between 2003 and 2008. There were 3663 submissions from 151 slaughterhouses of which 2470 (67.4%) were confirmed as culture positive for M. bovis. Logistic regression analysis with a random intercept for slaughterhouse was used to investigate relationships between bTB confirmation and animal and herd-level risk factors. Slaughterhouse of post mortem and the following factors related to bTB prevalence were significant predictors of confirmation probability: region of farm of origin of the animal, the testing interval for routine field surveillance for bTB on the farm, number of reactors in the last bTB incident on the farm within the last 4 years, if applicable, the animal's date of birth and the year of animal's slaughter. The modelled predicted population averaged probabilities for confirmation varied from 0.14 to 0.90 between slaughterhouses. Differences in the detection of cattle with bTB between British slaughterhouses warrant further study.

Bovine tuberculosis trends in the UK and the Republic of Ireland, 1995-2010.

Selected demographic features and trends in bovine tuberculosis (BTB) from 1995 to 2010 are described for the countries of the UK and the Republic of Ireland, using standardised definitions and measures. All countries experienced a reduction in the number of cattle and herds and in the proportion of dairy herds, while average herd size increased. In general, the trends indicate a stable situation of very low BTB prevalence in Scotland and, over most of the period, a rising prevalence in England and Wales. The prevalence in the Republic of Ireland declined while Northern Ireland experienced both a rise and fall. Differences in demography, BTB programme structure and test results were noted, particularly between the island of Ireland and Great Britain. Further investigation of these differences may provide valuable insights into risk factors for BTB and optimisation of existing BTB programmes.

Tuberculin manufacturing source and breakdown incidence rate of bovine tuberculosis in British cattle, 2005-2009.

The single intradermal comparative cervical tuberculin (SICCT) test is the primary test used for surveillance for bovine tuberculosis (bTB) in cattle in Great Britain (GB). The tuberculin used can, with other factors, influence test accuracy. In this analysis, the detection of infected cattle in GB 2005-2009 was compared between SICCT tests using tuberculins manufacturered by different manufacturers. Higher rates of reactors (adjusted rate 209 vs 186 per 100,000 tests, P = 0.003) and herd bTB incidents (adjusted total breakdown rate 5.1 vs 4.5 per 100 herd-years at risk, P < 0.001) were detected using tuberculin manufactured at Weybridge compared with Lelystad. However, confirmation of infection in reactors by postmortem evidence was higher with Lelystad tuberculin (adjusted percent 44.1 vs 47.1, P = 0.018). The findings, overall, suggest slightly higher test sensitivity and lower test specificity associated with Weybridge tuberculin compared with Lelystad. Assuming effective adjustment for confounding, the overall impact of tuberculin manufacturing source (2007-2009), was calculated to range somewhere between 315 false positive breakdowns, and 1086 bTB breakdowns missed (624 confirmed) as a result of using Weybridge and Lelystad tuberculin, respectively. However, animals that tested negative to the SICCT were not slaughtered at the time of the tests, so definitive conclusions are not possible.

HMOX1 and GST variants modify attenuation of FEF25-75% decline due to PM10 reduction.

Reduced exposure to particulate matter with a 50% cut-off aerodynamic diameter of 10 microm (PM(10)) attenuated age-related lung function decline in our cohort, particularly in the small airways. We hypothesised that polymorphisms in glutathione S-transferase (GST) and haem oxygenase-1 (HMOX1) genes, important for oxidative stress defence, modify these beneficial effects. A population-based sample of 4,365 adults was followed up after 11 yrs, including questionnaire, spirometry and DNA blood sampling. PM(10) exposure was estimated by dispersion modelling and temporal interpolation. The main effects on annual decline in forced expiratory flow at 25-75% of forced vital capacity (FEF(25-75%)) and interactions with PM(10) reduction were investigated for polymorphisms HMOX1 rs2071746 (T/A), rs735266 (T/A) and rs5995098 (G/C), HMOX1 (GT)(n) promoter repeat, GSTM1 and GSTT1 deletions, and GSTP1 p.Ile105Val, using mixed linear regression models. HMOX1 rs5995098, HMOX1 haplotype TTG and GSTP1 showed significant genetic main effects. Interactions with PM(10) reduction were detected: a 10 microg.m(-3) reduction significantly attenuated annual FEF(25-75%) decline by 15.3 mL.s(-1) only in the absence of HMOX1 haplotype ATC. Similarly, carriers of long (GT)(n) promoter repeat alleles or the GSTP1 Val/Val genotype profited significantly more from a 10 microg.m(-3) reduction (26.5 mL.s(-1) and 27.3 mL.s(-1) respectively) than non-carriers. Benefits of a reduction in PM(10) exposure are not equally distributed across the population but are modified by the individual genetic make-up determining oxidative stress defence.

Evidence of genetic resistance of cattle to infection with Mycobacterium bovis.

Anecdotal evidence points to genetic variation in resistance of cattle to infection with Mycobacterium bovis, the causative agent of bovine tuberculosis (BTB), and published experimental evidence in deer and cattle suggests significant genetic variation in resistance and reactivity to diagnostic tests. However, such genetic variation has not been properly quantified in the United Kingdom dairy cattle population; it is possible that it exists and may be a factor influencing the occurrence of BTB. Using models based on the outcome of the process of diagnosis (ultimate fate models) and on the outcome of a single stage of diagnosis (continuation ratio models, herd test-date models), this study shows that there is heritable variation in individual cow susceptibility to BTB, and that selection for milk yield is unlikely to have contributed to the current epidemic. Results demonstrate that genetics could play an important role in controlling BTB by reducing both the incidence and the severity of herd breakdowns.

Trace micro-nutrients may affect susceptibility to bovine tuberculosis in cattle.

Bovine tuberculosis (bTB) is a continuing problem in British herds. Micro-nutrients are important for the maintenance of well-functioning immune system. The aim of this study was to determine whether the selenium, copper and vitamin B12 status of cattle was associated with Mycobacterium bovis (M. bovis) infection. Between 2002 and 2005, 200 cattle (43% dairy, mean age 4.6 years), reactors according to the standard interpretation of the tuberculin test, and 200 in-contacts (41% dairy, mean age 4.4 years) non-reactors, which had been in contact with cattle with bTB, were selected from herds in England and Wales. Levels of the seleno enzyme glutathione peroxidase (GSHPx), copper and vitamin B12 were measured in blood. Confirmation of bTB infection was made by bacteriological culture and histopathology following a detailed postmortem. Levels of selenium and copper were also measured in a random sample of 63 livers. bTB was confirmed by culture/histology in 23/200 (11.5%) of in-contacts and 110/200 (55%) of reactors. In blood drawn at recruitment, GSHPx was lower in cattle with confirmed bTB compared to other cattle (geometric means 59.7 u/mL versus 78.9 u/mL red blood cells (RBC), p<0.01). Vitamin B12 was similar (geometric means 161.5 pmol/L versus 165.5 pmol/L, p=0.62) and copper was similar (geometric means 14.4 micromol/L versus 14.1 micromol/L, p=0.55). In logistic regression models including all micro-nutrients simultaneously and controlling for age, sex, animal production class, herd size, number of reactors, postmortem laboratory and seasonal trends, lower levels of GSHPx (adjusted OR 0.42, 95% CI 0.21-0.81 per 100 u/mL RBC, p=0.01) and higher levels of copper (adjusted OR 1.69, 95% CI 1.21-2.36 per 5 micromol/L, p<0.01) were associated with an increased risk of confirmed bTB but there was no association with vitamin B12. There was evidence for a stronger association between confirmed bTB and GSHPx in in-contacts (adjusted OR 0.21, 95% CI 0.06-0.79 per 100 u/mL RBC) compared to reactors (adjusted OR 0.50, 95% CI 0.21-1.23 per 100 u/mL RBC) (p=0.08 for interaction). Lower liver copper was associated with a higher risk of confirmed bTB (adjusted OR 0.15, 95% CI 0.02-1.0 per 5,000 micromol/kgdry mass, p=0.05) but there was no association between liver selenium and bTB. Trace micro-nutrient status may affect susceptibility to M. bovis infection in cattle. Further studies are needed.

Glutathione S-transferase genotype increases risk of progression from bronchial hyperresponsiveness to asthma in adults.

BACKGROUND: Bronchial hyperresponsiveness (BHR) and variation in glutathione S-transferase (GST) genes have been associated with asthma risk. The relationship of these two risk factors with adult onset asthma in the general population was investigated. METHODS: GSTP1 Ile105Val single nucleotide polymorphism and GSTM1 and GSTT1 gene deletion polymorphisms were genotyped in the population-representative SAPALDIA cohort. BHR was assessed at baseline by methacholine challenge and defined as a fall of > or =20% in forced expiratory volume in 1 s. Independent effects of GST polymorphisms and BHR on new onset of asthma after 11 years of follow-up were estimated by multiple logistic regression analysis, adjusting for relevant baseline measures. Effect modification was assessed by including interaction terms in the model. RESULTS: Among 4426 asthma-free participants at baseline, 14% had BHR. At follow-up, 3.3% reported new onset of physician-diagnosed asthma. BHR (p<0.001) and GSTP1 Ile105Val genotype (p = 0.005) were independently associated with incident asthma, but no association was seen for GSTT1 and GSTM1 gene deletion polymorphisms. Among subjects free of respiratory symptoms at baseline, the effect of BHR on the risk of physician-diagnosed asthma at follow-up was restricted to GSTP1 105 Ile/Ile carriers (OR 4.57, 95% CI 2.43 to 8.57 vs 1.40, 95% CI 0.58 to 3.39; p for interaction = 0.023). CONCLUSIONS: If confirmed by independent studies, our results suggest that GSTP1 Ile105Val genotype strongly determines the progression of BHR to physician-diagnosed asthma in the general population.

Pathology of naturally occurring bovine tuberculosis in England and Wales.

The aim of this study was to obtain a contemporary data set of pathology in tuberculin reactor and in-contact cattle in England and Wales. Four hundred animals (200 reactors and 200 in-contacts) from 242 farms located in 14 counties in Western England and Wales were examined. The mean number of lymph nodes (LNs) with tuberculosis (TB)-like lesions per TB-confirmed animal was 1.7 in reactors and 1.5 in in-contact animals. Tuberculous lesions in both reactor and in-contact animals were most commonly observed in the LNs of the thorax, followed by the head and abdomen, particularly the mediastinal, retropharyngeal and tracheobronchial LNs. Twenty-five reactors had macroscopic lesions in the palatine tonsils. Among TB-confirmed cattle, 27% of reactors and 9% of in-contact animals had gross TB-like lesions in the lungs, particularly in the caudal lobes. Gross lesions that were not TB-confirmed were parasitic granulomas (45%), bacterial or mycotic club-forming pyogranulomas (27%) and bacterial abscesses (23%). Diagnostic sensitivity was maximised when bacteriology and histopathology were used concurrently. Stage IV granulomas, alone or in combination with other stages, constituted 63% of lesions, while 16% of lesions were stage I/II granulomas. Caseous necrosis and calcification were common features of the granulomas encountered in natural Mycobacterium bovis infections, even with pathology limited to a small number of sites. Granulomas often covered large areas of histological sections and typically contained only small numbers of acid fast bacilli.