Co-infection of cattle with Fasciola hepatica or F. gigantica and Mycobacterium bovis: A systematic review

Autoři: Alison K. Howell aff001;  Catherine M. McCann aff001;  Francesca Wickstead aff002;  Diana J. L. Williams aff001
Působiště autorů: Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom aff001;  School of Veterinary Science, University of Liverpool, Leahurst, Neston, United Kingdom aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pone.0226300


The liver flukes, Fasciola hepatica and F. gigantica, are common trematode parasites of livestock. F. hepatica is known to modulate the immune response, including altering the response to co-infecting pathogens. Bovine tuberculosis (bTB), caused by Mycobacterium bovis, is a chronic disease which is difficult to control and is of both animal welfare and public health concern. Previous research has suggested that infection with liver fluke may affect the accuracy of the bTB skin test, but direction of the effect differs between studies. In a systematic review of the literature, all experimental and observational studies concerning co-infection with these two pathogens were sought. Data were extracted on the association between fluke infection and four measures of bTB diagnosis or pathology, namely, the bTB skin test, interferon γ test, lesion detection and culture/bacterial recovery. Of a large body of literature dating from 1950 to 2019, only thirteen studies met the inclusion criteria. These included studies of experimentally infected calves, case control studies on adult cows, cross sectional abattoir studies and a herd level study. All the studies had a medium or high risk of bias. The balance of evidence from the 13 studies included in the review suggests that liver fluke exposure was associated with either no effect or a decreased response to all of the four aspects of bTB diagnosis assessed: skin test, IFN γ, lesion detection and mycobacteria cultured or recovered. Most studies showed a small and/or non-significant effect so the clinical and practical importance of the observed effect is likely to be modest, although it could be more significant in particular groups of animals, such as dairy cattle.

Klíčová slova:

Cattle – Co-infections – Enzyme-linked immunoassays – Immune response – Interferons – Lesions – Observational studies – Skin tests


1. Mehmood K, Zhang H, Sabir AJ, Abbas RZ, Ijaz M, Durrani AZ, et al. A review on epidemiology, global prevalence and economical losses of fasciolosis in ruminants. Microb Pathog. 2017;109: 253–262. doi: 10.1016/j.micpath.2017.06.006 28602837

2. Clery D, Torgerson P, Mulcahy G. Immune responses of chronically infected adult cattle to Fasciola hepatica. Vet Parasitol. 1996;62: 71–82. doi: 10.1016/0304-4017(95)00858-6 8638395

3. Gazzinelli R, Oswald I, James S, Sher A. IL-10 inhibits parasite killing and nitrogen oxide production by IFN-gamma-activated macrophages. J Immunol. 1992;148: 1792–6. Available: 1541819

4. Flynn RJ, Mulcahy G. The roles of IL-10 and TGF-beta in controlling IL-4 and IFN-gamma production during experimental Fasciola hepatica infection. Int J Parasitol. 2008;38: 1673–80. doi: 10.1016/j.ijpara.2008.05.008 18597757

5. McCole DF, Doherty ML, Baird AW, Davies WC, McGill K, Torgerson PR. T cell subset involvement in immune responses to Fasciola hepatica infection in cattle. Parasite Immunol. 1999;21: 1–8. doi: 10.1046/j.1365-3024.1999.00188.x 10081766

6. Altmann DM. Review series on helminths, immune modulation and the hygiene hypothesis: nematode coevolution with adaptive immunity, regulatory networks and the growth of inflammatory diseases. Immunology. 2009;126: 1–2. doi: 10.1111/j.1365-2567.2008.03006.x 19120492

7. Moreau E, Chauvin A. Immunity against Helminths: Interactions with the Host and the Intercurrent Infections. J Biomed Biotechnol. 2010; doi: 10.1155/2010/428593 20150967

8. Rapsch C, Schweizer G, Grimm F, Kohler L, Bauer C, Deplazes P, et al. Estimating the true prevalence of Fasciola hepatica in cattle slaughtered in Switzerland in the absence of an absolute diagnostic test. Int J Parasitol. 2006;36: 1153–1158. doi: 10.1016/j.ijpara.2006.06.001 16843470

9. Mazeri S, Sargison N, Kelly RF, Bronsvoort BM., Handel I, Brennan G. Evaluation of the performance of five diagnostic tests for Fasciola hepatica infection in naturally infected cattle using a Bayesian no gold standard approach. Yu X, editor. PLoS One. CABI publishing; 2016;11: e0161621. doi: 10.1371/journal.pone.0161621 27564546

10. Charlier J, De Meulemeester L, Claerebout E, Williams D, Vercruysse J. Qualitative and quantitative evaluation of coprological and serological techniques for the diagnosis of fasciolosis in cattle. Vet Parasitol. 2008;153: 44–51. doi: 10.1016/j.vetpar.2008.01.035 18329811

11. Salimi-Bejestani MR, McGarry JW, Felstead S, Ortiz P, Akca A, Williams DJL. Development of an antibody-detection ELISA for Fasciola hepatica and its evaluation against a commercially available test. Res Vet Sci. 2005;78: 177–181. doi: 10.1016/j.rvsc.2004.08.005 15563926

12. O’Reilly LM, Daborn CJ. The epidemiology of Mycobacterium bovis infections in animals and man: a review. Tuber Lung Dis. 1995;76 Suppl 1: 1–46. Available:

13. Pollock JM, Neill SD. Mycobacterium bovis infection and tuberculosis in cattle. Vet J. 2002;163: 115–127. doi: 10.1053/tvjl.2001.0655 12093187

14. Podinovskaia M, Lee W, Caldwell S, Russell DG. Infection of macrophages with Mycobacterium tuberculosis induces global modifications to phagosomal function. Cell Microbiol. 2013;15: 843–59. doi: 10.1111/cmi.12092 23253353

15. Flynn JL, Chan J, Triebold KJ, Dalton DK, Stewart TA, Bloom BR. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993;178: 2249–54. Available: doi: 10.1084/jem.178.6.2249 7504064

16. Tufariello JM, Chan J, Flynn JL. Latent tuberculosis: mechanisms of host and bacillus that contribute to persistent infection. LANCET Infect Dis. 2003;3: 578–590. Available: doi: 10.1016/s1473-3099(03)00741-2 12954564

17. McGill JL, Sacco RE, Baldwin CL, Telfer JC, Palmer M V, Waters WR. The role of gamma delta T cells in immunity to Mycobacterium bovis infection in cattle. Vet Immunol Immunopathol. 2014;159: 133–43. doi: 10.1016/j.vetimm.2014.02.010 24636303

18. Welsh MD, Cunningham RT, Corbett DM, Girvin RM, McNair J, Skuce RA, et al. Influence of pathological progression on the balance between cellular and humoral immune responses in bovine tuberculosis. Immunology. Blackwell Science Ltd; 2005;114: 101–111. doi: 10.1111/j.1365-2567.2004.02003.x 15606800

19. Liebana E, Johnson L, Gough J, Durr P, Jahans K, Clifton-Hadley R, et al. Pathology of naturally occurring bovine tuberculosis in England and Wales. Vet J. 2008;176: 354–360. doi: 10.1016/j.tvjl.2007.07.001 17728162

20. Anon. Bovine tuberculosis. OIE Terrestrial Manual. OIE; 2018. Available:

21. Anon. USDA APHIS | Tuberculosis [Internet]. 2017 [cited 27 Sep 2019]. Available:

22. Anon. EU Council Directive on animal health problems affecting intra-Community trade in bovines and swine [Internet]. 1964 [cited 27 Sep 2019]. Available:

23. de la Rua-Domenech R, Goodchild AT, Vordermeier HM, Hewinson RG, Christiansen KH, Clifton-Hadley RS. Ante mortem diagnosis of tuberculosis in cattle: A review of the tuberculin tests, gamma-interferon assay and other ancillary diagnostic techniques. Res Vet Sci. 2006;81: 190–210. doi: 10.1016/j.rvsc.2005.11.005 16513150

24. Karolemeas K, McKinley TJ, Clifton-Hadley RS, Goodchild A V, Mitchell A, Johnston WT, et al. Recurrence of bovine tuberculosis breakdowns in Great Britain: Risk factors and prediction. Prev Vet Med. 2011;102: 22–29. doi: 10.1016/j.prevetmed.2011.06.004 21767886

25. Neill SD, Bryson DG, Pollock JM. Pathogenesis of tuberculosis in cattle. Tuberculosis. 2001;81: 79–86. doi: 10.1054/tube.2000.0279 11463227

26. Strain SAJ, McNair J, McDowell SWJ. Bovine tuberculosis: A review of diagnostic tests for M. bovis infection in cattle [Internet]. 2011. Available:

27. Anon. Bovine tuberculosis: OIE—World Organisation for Animal Health [Internet]. [cited 27 Sep 2019]. Available:

28. The Cochrane Collaboration. Cochrane Handbook for Systematic Reviews of Interventions [Internet]. Version 5. Higgins J, Green S, editors. 2011. Available:

29. Bennema SC, Ducheyne E, Vercruysse J, Claerebout E, Hendrickx G, Charlier J. Relative importance of management, meteorological and environmental factors in the spatial distribution of Fasciola hepatica in dairy cattle in a temperate climate zone. Int J Parasitol. 2011;41: 225–233. doi: 10.1016/j.ijpara.2010.09.003 20887726

30. Olsen A, Frankena K, Bødker R’, Toft N, Thamsborg SM, Enemark HL, et al. Prevalence, risk factors and spatial analysis of liver fluke infections in Danish cattle herds. 2011; doi: 10.1186/s13071-015-0773-x 25888827

31. Bessell PR, Orton R, White PCL, Hutchings MR, Kao RR. Risk factors for bovine Tuberculosis at the national level in Great Britain. BMC Vet Res. 2012;8: 51. doi: 10.1186/1746-6148-8-51 22564214

32. Skuce RA, Allen AR, McDowell SWJ. Herd-level risk factors for bovine tuberculosis: a literature review. Vet Med Int. 2012;2012: 621210. doi: 10.1155/2012/621210 22966479

33. Ogilvie D, Fayter D, Petticrew M, Sowden A, Thomas S, Whitehead M, et al. The harvest plot: A method for synthesising evidence about the differential effects of interventions. BMC Med Res Methodol. BioMed Central; 2008;8: 8. doi: 10.1186/1471-2288-8-8 18298827

34. Schanzel H, Stolarik L. The influence of liver flukes on the specificity of the intradermal tuberculin test in cattle. Vet Med Praha. 1962;7: 39.

35. Meyer W. Hetero-allergy to the tuberculin reaction in cattle. Monatsh Veterinarmed. 1963;18: 325–328.

36. DEFRA. Report on TB SE3013. 2005.

37. Broughan JM, Durr P, Clifton-Hadley R, Colloff A, Goodchild T, Sayers R, et al. Bovine tuberculosis and Fasciola hepatica infection. Proceedings of the Society of Veterinary Epidemiology and Preventive Medicine Conference 2009. London; 2009. Available:; Bovine tuberculosis and Fasciola hepatica infection.pdf

38. Flynn RJ, Mannion C, Golden O, Hacariz O, Mulcahy G. Experimental Fasciola hepatica Infection Alters Responses to Tests Used for Diagnosis of Bovine Tuberculosis. Infect Immun. 2007;75: 1373–1381. doi: 10.1128/IAI.01445-06 17194810

39. Garza-Cuartero L, Blanco A, Mcnair J, Flynn RJ, Williams D, Diggle P, et al. Fasciola hepatica Infection Reduces Mycobacterium and Mycobacterial Uptake Suppresses the Pro-inflammatory Response. Parasite Immunol. 2016;38: 387–402. doi: 10.1111/pim.12326 27108767

40. Flynn RJ, Mulcahy G, Welsh M, Cassidy JP, Corbett D, Milligan C, et al. Co-Infection of Cattle with Fasciola hepatica and Mycobacterium bovis—Immunological Consequences. Transbound Emerg Dis. 2009;56: 269–274. doi: 10.1111/j.1865-1682.2009.01075.x 19575746

41. Munyeme M, Munang’andu HM, Nambota A, Muma JB, Phiri AM, Nalubamba KS. The Nexus between Bovine Tuberculosis and Fasciolosis Infections in Cattle of the Kafue Basin Ecosystem in Zambia: Implications on Abattoir Surveillance. Vet Med Int. 2012;2012: 921869. doi: 10.1155/2012/921869 23213629

42. Claridge JA. Does Fasciola hepatica infection increase the susceptibility of cattle to infection with other pathogens normally controlled by a Th1 or pro-inflammatory response? This thesis has been submitted in accordance with the requirements of the University of Li. 2012;

43. Claridge J, Diggle P, McCann CM, Mulcahy G, Flynn R, McNair J, et al. Fasciola hepatica is associated with the failure to detect bovine tuberculosis in dairy cattle. Nat Commun. 2012;3. doi: 10.1038/ncomms1840 22617293

44. Byrne AW, Graham J, Brown C, Donaghy A, Guelbenzu-Gonzalo M, McNair J, et al. Bovine tuberculosis visible lesions in cattle culled during herd breakdowns: the effects of individual characteristics, trade movement and co-infection. BMC Vet Res. BioMed Central; 2017;13: 400. doi: 10.1186/s12917-017-1321-z 29284483

45. Byrne AW, Graham J, Brown C, Donaghy A, Guelbenzu-Gonzalo M, McNair J, et al. Modelling the variation in skin-test tuberculin reactions, post-mortem lesion counts and case pathology in tuberculosis-exposed cattle: Effects of animal characteristics, histories and co-infection. Transbound Emerg Dis. Wiley/Blackwell (10.1111); 2018;65: 844–858. doi: 10.1111/tbed.12814 29363285

46. Kelly RF, Callaby R, Egbe NF, Williams DJL, Victor NN, Tanya VN, et al. Association of Fasciola gigantica Co-infection With Bovine Tuberculosis Infection and Diagnosis in a Naturally Infected Cattle Population in Africa. Front Vet Sci. Frontiers; 2018;5: 214. doi: 10.3389/fvets.2018.00214 30238010

47. Byrne AW, McBride S, Graham J, Laheurta-Marin A, McNair J, Skuce R, et al. Liver fluke (Fasciola hepatica) co-infection with bovine tuberculosis (bTB) in cattle: a retrospective animal-level assessment of bTB risk in dairy and beef cattle. Transbound Emerg Dis. 2019; doi: 10.1111/tbed.13083 30484969

48. Byrne AW, Graham J, McConville J, Milne G, Guelbenzu-Gonzalo M, McDowell S. Liver fluke (Fasciola hepatica) co-infection with bovine tuberculosis (bTB) in cattle: a prospective herd-level assessment of herd bTB risk in dairy enterprises. Transbound Emerg Dis. 2019; doi: 10.1111/tbed.13209 31012527

49. Egbe NF, Muwonge A, Ndip L, Kelly RF, Sander M, Tanya V, et al. Abattoir-based estimates of mycobacterial infections in Cameroon. Nat Sci Reports. 2016;6. doi: 10.1038/srep24320 27075056

50. Dean GS, Rhodes SG, Coad M, Whelan AO, Cockle PJ, Clifford DJ, et al. Minimum infective dose of Mycobacterium bovis in cattle. Infect Immun. American Society for Microbiology; 2005;73: 6467–6471. doi: 10.1128/IAI.73.10.6467-6471.2005 16177318

51. Kokurichev PI, Karabainov MA. Specificity of the tuberculin test in cattle with fascioliasis. Sb Nauchnikh Tr Leningr Inst Usovershenstvovaniya Vet Vrachei. 1957;11: 81–85. Available:

52. Manukyan ZK. Non-specific tuberculin reactions in cattle with fascioliasis. Tr Armyanskogo Nauchno-Issledovatelskogo Vet Instituta. 1955;8: 25–28. Available:

53. El-Ahwal AMA. [Effect of experimental fascioliasis on the results of the intradermal tuberculin test in the guinea pig]. Berliner und Münchener tierärztliche Wochenschrift. 1969;82: 484–5. Available: 5399020

54. Hartwigt H, El-Ahwal AMA. Untersuchungen ueber die bedeutung der Fasciolose als Ursache positiver Tuberkulinreaktionen beim Rind. Berliner und Muenchener Tieraerztliche Wochenschrift1. 1968;81: 315–316.

55. Bossaert K, Farnir F, Leclipteux T, Protz M, Lonneux JF, Losson B. Humoral immune response in calves to single-dose, trickle and challenge infections with Fasciola hepatica. Vet Parasitol. 2000;87: 103–23. Available: doi: 10.1016/s0304-4017(99)00177-6 10622602

56. Hayward AD, Garnier R, Watt KA, Pilkington JG, Grenfell BT, Matthews JB, et al. Heritable, Heterogeneous, and Costly Resistance of Sheep against Nematodes and Potential Feedbacks to Epidemiological Dynamics. Am Nat. 2014;184: S58–S76. doi: 10.1086/676929 25061678

57. Jolles AE, Ezenwa VO, Etienne RS, Turner WC, Olff H. Interactions between macroparasites and microparasites drive infection patterns in free-ranging African buffalo. Ecology. 2008;89: 2239–2250. doi: 10.1890/07-0995.1 18724734

58. Ezenwa VO, Jolles AE. Opposite effects of anthelmintic treatment on microbial infection at individual versus population scales. Science (80-). 2014;347: 175–7.

59. Fenton A, Knowles SCL, Petchey OL, Pedersen AB. The reliability of observational approaches for detecting interspecific parasite interactions: Comparison with experimental results. Int J Parasitol. Australian Society for Parasitology Inc.; 2014;44: 437–445. doi: 10.1016/j.ijpara.2014.03.001 24704058

60. Howell A, Baylis M, Smith R, Pinchbeck G, Williams D. Epidemiology and impact of Fasciola hepatica exposure in high-yielding dairy herds. Prev Vet Med. Elsevier B.V.; 2015;121: 41–48. doi: 10.1016/j.prevetmed.2015.05.013 26093971

61. McCann CM, Baylis M, Williams DJL. Seroprevalence and spatial distribution of Fasciola hepatica-infected dairy herds in England and Wales. Vet Rec. BioMed Central; 2010;166: 612–617. doi: 10.1136/vr.b4836 20472872

62. Bloemhoff Y, Forbes A, Danaher M, Good B, Morgan E, Mulcahy G, et al. Determining the Prevalence and Seasonality of Fasciola hepatica in Pasture-based Dairy herds in Ireland using a Bulk Tank Milk ELISA. Ir Vet J. 2015;68: 16. doi: 10.1186/s13620-015-0042-5 26157575

63. Abernethy DA, Upton P, Higgins IM, McGrath G, Goodchild A V, Rolfe SJ, et al. Bovine tuberculosis trends in the UK and the Republic of Ireland, 1995–2010. Vet Rec. 2013;172. doi: 10.1136/vr.100969 23292950

64. Allen AR, Skuce RA, Byrne AW. Bovine Tuberculosis in Britain and Ireland–A Perfect Storm? the Confluence of Potential Ecological and Epidemiological Impediments to Controlling a Chronic Infectious Disease. Front Vet Sci. Frontiers; 2018;5: 109. doi: 10.3389/fvets.2018.00109 29951489

65. Caminade C, Van Dijk J, Baylis M, Williams D. Modelling recent and future climatic suitability for fasciolosis in Europe. Geospat Health. 2015;9: 301. doi: 10.4081/gh.2015.352 25826311

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