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Caseous lymphadenitis
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Small Ruminant Research 76 (2008) 42–48
Caseous lymphadenitis夽 M.C. Fontaine a,∗ , G.J. Baird b a
Moredun Research Institute, International Research Centre, Pentlands Science Park, Bush Loan, Penicuik EH26 0PZ, Scotland, UK b SAC Veterinary Services, 5 Bertha Park View, Perth PH1 3FZ, Scotland, UK
Abstract Caseous lymphadenitis has been a prevalent disease among farmed small ruminants in the majority of sheep-rearing countries for over a century. As it is a chronic disease, introduction of control measures in many countries has been slow or absent, resulting in a steady increase in the incidence of the disease. This, in turn, has impacted upon producers with respect to significant economic losses, not to mention issues of animal welfare, through (in extreme cases) chronic ill-thrift, carcase condemnation at abattoirs and reduced wool yields. This short review presents an overview of the current status of research on caseous lymphadenitis, with special reference to transmission of disease, pathology and pathogenesis. © 2008 Elsevier B.V. All rights reserved. Keywords: Sheep; Caseous lymphadenitis; CLA; Corynebacterium pseudotuberculosis
1. Introduction The Gram-positive actinomycete, Corynebacterium pseudotuberculosis, is a cause of chronic infections in a number of different mammalian species, the most significant of which is caseous lymphadenitis (abbreviated either to CLA or CL) of farmed small ruminants. The significance of the disease is evidenced by the scientific research and political debate which has been ongoing in relation to this topic for over a century. Other animal species in which infection with C. pseudotuberculosis is relatively common, include horses (Addo et al., 1974; Miers and Ley, 1980; Poonacha and Donahue, 1995), cattle (Purchase, 1944; Adekeye et al., 1980; Kariuki and Poulton, 1982; Anderson et al., 1990; Shpigel et al., 1993; Yeruham et al., 1997), 夽 This paper is part of the special issue entitled “Current issues in Sheep Health and Welfare guest edited by George C. Fthenakis. ∗ Corresponding author. E-mail address: [email protected] (M.C. Fontaine).
0921-4488/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.smallrumres.2007.12.025
llamas and alpacas (Braga et al., 2006, 2007) and buffalo (Ali and Zaitoun, 1999). In addition, while not as common, C. pseudotuberculosis infection of humans has been reported on several occasions (Lopez et al., 1966; Hamilton et al., 1968; Hill et al., 1978; Henderson, 1979; Keslin et al., 1979; Goldberger et al., 1981; House et al., 1986; Mills et al., 1997; Peel et al., 1997; Join-Lambert et al., 2006), making the disease a potential zoonosis. Following invasion of the host by C. pseudotuberculosis, the organism becomes encapsulated within walled-off lesions from where it evades immune system-mediated destruction, giving rise to a state of persistent infection. This is in contrast to many diseases of veterinary importance characterized by acute and often lethal infections. However, despite the apparent containment of the pathogen within these lesions, the disease is contagious enough to infect the majority of sheep in a flock. 2. Pathogenesis and transmission Infection of small ruminants with C. pseudotuberculosis usually results in the formation of pyogranuloma-
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Fig. 2. Multiple caseous lesions within the lungs. Fig. 1. A ruptured caseous lymphadenitis abscess within the parotid lymph node; there is also loss of overlying hair.
tous lesions (Valli and Parry, 1993), which present in two different ways. The external, also known as cutaneous or superficial, form of CLA is characterized by the development of abscesses within the superficial lymph nodes (Fig. 1) or within the subcutaneous tissue. In either case, abscesses may develop over significant periods of time, becoming swollen and encased within fibrous capsules, resulting finally in the loss of overlying hair and often rupturing (Radostits et al., 2000). Significantly, the purulent contents of ruptured lesions are an important source of cross-infection between animals, since the number of viable organisms contained within pus is between 1 × 106 and 5 × 107 c.f.u./g (Brown and Olander, 1987). Therefore, abscess rupture releases huge numbers of bacteria onto the skin and fleece, resulting in the subsequent contamination of the immediate environment. Neighbouring animals may then be exposed to bacteria, either through direct physical contact with the affected individual or indirectly via contaminated fomites. The second form of CLA manifestation is a visceral form, characterized by the formation of lesions within the animal, which cannot be observed externally. The site of these lesions is commonly the internal lymph nodes (primarily the mediastinal lymph nodes) or lungs (Fig. 2), although other tissues may also be affected. These include primarily the liver, the kidneys or the mammary glands and less frequently the heart, the brain, the spinal cord, the testes, the uterus and the joints (Valli and Parry, 1993). A respiratory route for transfer of C. pseudotuberculosis infection has been postulated (Stoops et al., 1984) and some research suggests that animals with pulmonary lesions may present the major source of exposure to na¨ıve animals within a flock (Ellis et al., 1987; Paton et al., 1988; Pepin et al., 1994; Williamson, 2001). This hypothesis derives from the
observation that lung lesions are not uncommon among infected animals and in some cases appear to be the only site of infection. Pulmonary lesions may be found within the walls of airways, leading to the hypothesis that abscess rupture could result in the production of an infectious aerosol (Stoops et al., 1984; Pepin et al., 1994). In animals with pulmonary abscesses, CLA lesions may also be found within the mediastinal and bronchial lymph nodes, implying migration from the lung parenchyma. Significantly, abscesses within the mediastinal lymph nodes may exert pressure upon the adjacent oesophagus as they grow in size, eventually interfering with normal swallowing and rumination, resulting in chronic ill-thrift (Paton et al., 2005). Although experimental C. pseudotuberculosis infection within the lungs of sheep has been achieved by intratracheal administration of bacteria (Brown and Olander, 1987), more recent studies suggest that pulmonary lesions develop as part of a systemic infection initiated elsewhere in the body. This latter hypothesis would appear to be strengthened by the observation that following experimental inoculation of C. pseudotuberculosis by the intravenous route, the major proportion of internal lesions are found within the lungs and associated thoracic lymph nodes (Brogden et al., 1984). Furthermore, sub-cutaneous inoculation of C. pseudotuberculosis has also been shown to result in formation of multiple infection foci at sites distinct from the initial site of inoculation, including the lungs and mediastinal lymph nodes (Fontaine et al., 2006). In natural cases of CLA, it has been observed that the patterns of distribution of pulmonary lesions are consistent with the theory of haematogenous or lymphogenous spread rather than aerogenous (Nairn and Robertson, 1974). Nevertheless, anecdotal evidence for the aerogenous transmission of C. pseudotuberculosis persists, warranting further research in this area.
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In addition to the intratracheal route described above, sheep have been experimentally infected with C. pseudotuberculosis by inoculation of the organism via the intradermal, subcutaneous, intralymphatic, intravenous, intratracheal and intravaginal routes (Nagy, 1976; Burrell, 1978; Pepin et al., 1994; Fontaine et al., 2006). In naturally observed infections, the main portal of bacterial entry is generally accepted to be through the skin, normally as a result of the presence of minor wounds and abrasions (Batey, 1986b; Brown and Olander, 1987; Davis, 1990; Collett et al., 1994). In many countries, shearing is considered to be a major risk factor in the spread of infection between animals (Nagy, 1976; Paton et al., 1988; Serikawa et al., 1993; Paton et al., 1996; Al Rawashdeh and Al Qudah, 2000), particularly because of wounds that arise during the shearing process and because C. pseudotuberculosis can be transferred on shearing equipment (Paton et al., 1988). If subsequent decontamination measures are inadequate, it is possible that shearing gear, clothing and mobile handling equipment may also serve to transfer infection between flocks. Iatrogenic wounds (as a result of castration and docking) and the umbilicus in neonatal sheep have also been suggested as routes by which C. pseudotuberculosis can gain entry to the host (Valli and Parry, 1993). In addition, head and neck lesions, limited in number in Australian and North American sheep but more frequent in goats, are thought to arise from bacterial entry via the oral cavity (Ashfaq and Campbell, 1979). In the UK, CLA abscesses in sheep tend to be associated primarily with the lymph nodes of the head and neck, which is a similar presentation to that in goats elsewhere in the world (Baird, 2003). However, in small ruminants outwith the UK, the disease primarily affects the superficial lymph nodes of the torso (Nagy, 1971; Ayers, 1977; Stoops et al., 1984; Batey, 1986a; Brown and Olander, 1987; Nuttall, 1988; Muckle and Menzies, 1993; Collett et al., 1994; Williamson, 2001; ChirinoZ´arraga et al., 2006). Based upon what is known of the pathogenesis of CLA, it would therefore seem that the location of superficial lesions is dependent on where the initial point of C. pseudotuberculosis entry occurred, resulting in migration to the local drainage lymph node. In addition to the more frequently encountered manifestations of C. pseudotuberculosis infection described above, the organism may occasionally be the causative agent of mastitis. This condition is most likely to arise as a result of the progression of infection from the supra-mammary lymph node, and may manifest as acute, suppurative mastitis, or alternatively as chronic encapsu-
lated abscesses within the mammary gland. In addition, on rare occasions the organism has also been identified within the stomach contents and tissues of ovine foetuses and has been implicated as a cause of abortion (Dennis and Bamford, 1966). 3. Pathology Following entry into the host through the skin, C. pseudotuberculosis normally migrates to the local drainage lymph node to form microscopic pyogranulomas, which gradually increase in size, eventually combining to form larger abscesses. It has been suggested that carriage within phagocytes is the means by which the organism reaches the lymph node via the lymphatic drainage (Pepin et al., 1994). Dissemination of infection may also occur by transfer of the organism via the blood or lymphatic system and this may result in the formation of lesions at other loci within the host. The ability of the organism to resist immune clearance by the na¨ıve host and disseminate beyond the primary locus of infection is in part due to its ability to survive and replicate within macrophages (Williamson, 2001). Significantly, viable bacteria may routinely be recovered from within abscesses several years following the initial infection and the disease may become “reactivated” as a result of the dissemination of C. pseudotuberculosis after a significant period of apparent dormancy. The host cellular response to infection with C. pseudotuberculosis has been described in detail. In studies involving sheep challenged subcutaneously, vast numbers of neutrophils were shown to be enlisted to the site of inoculation within the first few hours following infection and from there began to move to the local drainage lymph node within 24 h. The importance of neutrophils was found to decrease after 3 days, while the numbers of macrophages at the inoculation site increased significantly (Pepin et al., 1992). A period of generalized inflammation of the lymph node was shown to follow infection and micro-abscesses developed within the cortical region of the node within 24 h of inoculation (Pepin et al., 1991); these became more numerous after approximately 6 days, from which point they began to enlarge and coalesce to form more significant purulent foci. These early pyogranulomas contained clumps of bacteria and cellular debris and a high proportion of eosinophils, giving a characteristic green colour to the purulent material. In addition and concurrently with the cellular response at the site of inoculation, the infiltration of neutrophils declined while monocytes/macrophages became the predominant cell type within the infected
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Fig. 4. Immunohistochemical analysis of the prescapular lymph node shown in Fig. 3, using rabbit anti-C. pseudotuberculosis IgG followed by haematoxylin staining (100× magnification). A zone of coagulative necrosis (A) is present towards the centre of the abscess, followed by a zone of immature fibrosis (B) throughout which bacteria can be visualised as brown dots, laid down in layers along the advancing front of the abscess. A zone of mature fibrosis is observed towards the surface of the abscess (C).
Fig. 3. (a) Transverse histological section of a caseous lymphadenitis lesion within an ovine prescapular lymph node (25 × 22 mm). Multiple concentric layers are discernible within the lymph node: liquifactive necrosis (liquid pus) is observed centrally (A), surrounded by coagulative necrosis (caseous pus; B), both containing multiple foci of mineralization (C); a thin layer of polymorphonuclear neutrophils enveloping the periphery of the coagulative necrosis with a further outer layer of coagulative necrosis containing polymorphonuclear neutrophils migrating through it at different densities and forming an apparent bi-layer (D), bordered by a layer of immature fibrosis delineating the extent of the lesion, in turn bordered by a layer of mature fibrosis (E); some scattered remnants of normal lymph node cortex present peripherally to this (F), surrounded by the thin, fibrous capsule enveloping a normal lymph node (G) (H&E, straight scan 1×). (b) Details of the section in (a) showing the various layers of the lesion. To the extreme right is the presence of liquifactive necrosis (A), followed by extensive coagulative necrosis (B), several foci of mineralization present within the necrotic tissue (dark blue/purple; C), the outer edge
node (Pepin et al., 1994). The lesion became encapsulated shortly afterwards (Fig. 3), resulting finally in a reduction in the inflammatory response within the parenchyma of the lymph node. Once infection has become established, gradual expansion of the lymph node may occur, dependant on its location and whether or not it ruptures to discharge its contents. Lymph node enlargement is brought about through a process of repeated necrosis of the lesion capsule, followed by its reformation. Initially, pus within the abscesses is soft and semi-fluid; however, over time this purulent material becomes more solid and scattered clumps of bacteria may be observed within it (Fig. 4). Small nodules of mineralization form within the purulent material, which cause it to become paler in colour. Additionally, these calcified foci tend to form in concentric layers, giving lesions a lamellated appearance, which is often described as being similar to the cross-sectional view of an onion. This “onion ring” presentation is characteristic in countries, where the disease has been endemic for a significant period of time.
of the necrosis with polymorphonuclear neutrophils (blue dots; D), also present in the immature fibrosis (light pink layer immediately adjacent to the necrotic pink tissue; E); presence of mononuclear inflammatory cells with the surrounding pale pink area being the mature fibrous tissue constituting the capsule of the abscess (F), with what little is left of the normal cortical lymph node tissue seen as aggregations of blue dots (G) and the normal capsule of the lymph node seen as the pale pink material outside this (H) (H&E, 20×).
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4. Distribution Interestingly, while CLA is a significant cause of economic loss and animal welfare problems in some countries, it appears to be relatively insignificant in others (although this may simply be due to under-reporting). Furthermore, while the disease has been resident in some parts of the world since the earliest reports in the late 19th century (e.g., Nocard, 1896; Pre¨ısz and Guinard, 1891), CLA is a new arrival to the United Kingdom, where it was first diagnosed in 1989 following the importation of infected goats (Lloyd et al., 1990; Meldrum, 1990). The disease is prevalent in much of Europe, Africa, the Middle East, Australasia and the Americas (Robins, 1991; Paton et al., 2005) and in many countries the disease has officially been an established problem of sheep for decades. A recent report has provided evidence of a close genotypic relationship between C. pseudotuberculosis isolates of ovine/caprine origin from different parts of the world (Connor et al., 2007), suggesting that the infection may have had a common source and supporting suggestions that the disease was spread around the world through the export of sheep by colonial powers (Paton, 2000). 5. Combating CLA The most efficient way of controlling CLA remains a matter of debate. Vaccination is the primary means of disease control in several countries, whereby immunisation reduces the spread of infection, leading to a gradual decline in disease prevalence. That said, no proprietary CLA vaccine currently available offers complete protection against infection by C. pseudotuberculosis; hence, the disease will continue to manifest, albeit at reduced level. This is evidenced by a report from Australia which indicated that, despite the widespread use of a commercial CLA vaccine in that country since 1983, disease prevalence remained at approximately 20% in 2002 (Paton et al., 2003). As an alternative to vaccination, serological diagnosis offers a powerful means of combating disease, through the culling/segregation of infected animals. This approach, while potentially costly in the first instance, is a means by which CLA may be completely eradicated from affected flocks. However, it is likely only to be of practical use in flocks that do not have a high incidence of the disease, given that the majority of farmers would not willingly relinquish the major portion of their animals. Therefore, it seems that a marriage of vaccination and serodiagnosis would provide the flexibility required for control of CLA. In this respect the continued develop-
ment of detection and vaccine reagents can only improve evolving control strategies. Acknowledgements The authors are grateful to Dr. Mark Dagleish and to Ms. Jeannie Finlayson of the Moredun Research Institute for the preparation and photography of histological sections. References Addo, P.B., Wilcox, G.E., Taussig, R., 1974. Mastitis in a mare caused by Corynebacterium ovis. Vet. Rec. 95, 193. Adekeye, J.D., Shannon, D., Addo, P.B., 1980. Mastitis in a cow caused by Corynebacterium pseudotuberculosis (C. ovis). Vet. Rec. 106, 270. Al Rawashdeh, O.F., Al Qudah, K.M., 2000. Effect of shearing on the incidence of caseous lymphadenitis in awassi sheep in Jordan. J. Vet. Med. B 47, 287–293. Ali, H.S., Zaitoun, A.M., 1999. Studies on cutaneous suppurative lymphangitis in buffaloes at Assiut Governorate-Egypt. Assiut. Vet. Med. J. 41, 208–222. Anderson, M.L., Lean, I.J., Blanchard, P.C., 1990. Corynebacterium pseudotuberculosis associated skin disease of Holstein cattle in the San Joaquin Valley, California. Bov. Pract. 25, 73–75. Ashfaq, M.K., Campbell, S.G., 1979. A survey of caseous lymphadenitis and its etiology in goats in the United States. Vet. Med. Small Anim. Clin. 74, 1161–1165. Ayers, J.L., 1977. Caseous lymphadenitis in goats and sheep: a review of diagnosis, pathogenesis, and immunity. J. Am. Vet. Med. Assist. 171, 1251–1254. Baird, G.J., 2003. Current perspectives on caseous lymphadenitis. In. Pract. 25, 62–68. Batey, R.G., 1986a. The effect of caseous lymphadenitis on body condition and weight of Merino mutton carcases. Aust. Vet. J. 63, 268. Batey, R.G., 1986b. Pathogenesis of caseous lymphadenitis in sheep and goats. Aust. Vet. J. 63, 269–272. Braga, W.U., Chavera, A., Gonzalez, A., 2006. Corynebacterium pseudotuberculosis infection in highland alpacas (Lama pacos) in Peru. Vet. Rec. 159, 23–24. Braga, W., Schul, S., Nu˜nez, A., Pezo, D., Franco, E., 2007. A primary Corynebacterium pseudotuberculosis low dose infection in alpacas (Lama pacos) protects against a lethal challenge exposure. Small Rumin. Res. 72, 81–86. Brogden, K.A., Cutlip, R.C., Lehmkuhl, H.D., 1984. Experimental Corynebacterium pseudotuberculosis infection in lambs. Am. J. Vet. Res. 45, 1532–1534. Brown, C.C., Olander, H.J., 1987. Caseous lymphadenitis of goats and sheep: a review. Vet. Bull. 57, 1–12. Burrell, D.H., 1978. Experimental induction of caseous lymphadenitis in sheep by intralymphatic inoculation of Corynebacterium ovis. Res. Vet. Sci. 24, 269–276. Chirino-Z´arraga, C., Scaramelli, A., Rey-Valeir´on, C., 2006. Bacteriological characterization of Corynebacterium pseudotuberculosis in Venezuelan goat flocks. Small Rumin. Res. 65, 170–175. Collett, M.G., Bath, G.F., Cameron, C.M., 1994. Corynebacterium pseudotuberculosis infections. In: Coetzer, J., Thomson, G.R., Tustin, R.C. (Eds.), Infectious Diseases of Livestock with Special
M.C. Fontaine, G.J. Baird / Small Ruminant Research 76 (2008) 42–48 Reference to Southern Africa, 2nd ed. Oxford University Press, Cape Town, pp. 1387–1395. Connor, K.M., Fontaine, M.C., Rudge, K., Baird, G.J., Donachie, W., 2007. Molecular genotyping of multinational ovine and caprine Corynebacterium pseudotuberculosis isolates using pulsed-field gel electrophoresis. Vet. Res. 38, 613–623. Davis, E.W., 1990. Corynebacterium pseudotuberculosis infections in animals. In: Smith, B.P. (Ed.), Large Animal Internal Medicine. Mosby, Toronto, pp. 1120–1126. Dennis, S.M., Bamford, V.W., 1966. The role of Corynebacteria in perinatal lamb mortality. Vet. Rec. 79, 105–108. Ellis, T.M., Sutherland, S.S., Wilkinson, F.C., Mercy, A.R., Paton, M.W., 1987. The role of Corynebacterium pseudotuberculosis lung lesions in the transmission of this bacterium to other sheep. Aust. Vet. J. 64, 261–263. Fontaine, M.C., Baird, G., Connor, K.M., Rudge, K., Sales, J., Donachie, W., 2006. Vaccination confers significant protection of sheep against infection with a virulent United Kingdom strain of Corynebacterium pseudotuberculosis. Vaccine 24, 5986– 5996. Goldberger, A.C., Lipsky, B.A., Plorde, J.J., 1981. Suppurative granulomatous lymphadenitis caused by Corynebacterium ovis (pseudotuberculosis). Am. J. Clin. Pathol. 76, 486–490. Hamilton, N.T., Perceval, A., Aarons, B.J., Goodyear, J.E., 1968. Pseudotuberculous axillary lymphadenitis caused by Corynebacterium pseudotuberculosis. Med. J. Aust. 2, 356–361. Henderson, A., 1979. Pseudotuberculous adenitis caused by Corynebacterium pseudotuberculosis. J. Med. Microbiol. 12, 147–149. Hill, L.R., Lapage, S.P., Bowie, I.S., 1978. Computer identification of coryneform bacteria. In: Bousefield, I.J., Callely, A.G. (Eds.), Coryneform Bacteria. Academic Press, London, pp. 181–215. House, R.W., Schousboe, M., Allen, J.P., Grant, C.C., 1986. Corynebacterium ovis (pseudotuberculosis) lymphadenitis in a sheep farmer: a new occupational disease in New Zealand. N. Z. Med. J. 99, 659–662. Join-Lambert, O.F., Ouache, M., Canioni, D., Beretti, J.-L., Blanche, S., Berche, P., Kayal, S., 2006. Corynebacterium pseudotuberculosis necrotizing lymphadenitis in a twelve-year-old patient. Pediatric. Infect. Dis. J. 25, 848–851. Kariuki, D.P., Poulton, J., 1982. Corynebacterium infection of cattle in Kenya. Trop. Anim. Health Prod. 14, 33–36. Keslin, M.H., McCoy, E.L., McCusker, J.J., Lutch, J.S., 1979. Corynebacterium pseudotuberculosis. A new cause of infectious and eosinophilic pneumonia. Am. J. Med. 67, 228–231. Lloyd, S., Lindsay, H.J., Slater, J.D., Jackson, P.G., 1990. Caseous lymphadenitis in goats in England. Vet. Rec. 127, 478. Lopez, J.F., Wong, F.M., Quesada, J., 1966. Corynebacterium pseudotuberculosis. First case of human infection. Am. J. Clin. Pathol. 46, 562–567. Meldrum, K.C., 1990. Caseous lymphadenitis outbreak. Vet. Rec. 126, 369. Miers, K.C., Ley, W.B., 1980. Corynebacterium pseudotuberculosis infection in the horse: study of 117 clinical cases and consideration of etiopathogenesis. J. Am. Vet. Med. Assist. 177, 250–253. Mills, A.E., Mitchell, R.D., Lim, E.K., 1997. Corynebacterium pseudotuberculosis is a cause of human necrotising granulomatous lymphadenitis. Pathology 29, 231–233. Muckle, C.A., Menzies, P.I., 1993. Caseous lymphadenitis in sheep and goats. In: Howard, J. (Ed.), Current Veterinary Therapy: Food Animal Practice, 3rd ed. Saunders, Philadelphia, pp. 537– 541.
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Nagy, G., 1971. Ticks and caseous lymphadenitis in sheep: preliminary observations. J. South Afr. Vet. Assist. 42, 227–232. Nagy, G., 1976. Caseous lymphadenitis in sheep—methods of infection. J. South Afr. Vet. Assist. 47, 197–199. Nairn, M.E., Robertson, J.P., 1974. Corynebacterium pseudotuberculosis infection of sheep: role of skin lesions and dipping fluids. Aust. Vet. J. 50, 537–542. Nocard, E., 1896. Ann. Pasteur. Inst. 10, 609. Nuttall, W., 1988. Caseous lymphadenitis in sheep and goats in New Zealand. Surveill. N. Z. 15, 10–12. Paton, M.W., 2000. Applying the experience of CLA in the southern hemisphere. In: Proceedings of the Moredun Research Institute/Scottish Agricultural College Workshop on Caseous Lymphadenitis, pp. 3–15. Paton, M.W., Collett, M.G., Pepin, M., Bath, G.F., 2005. Corynebacterium pseudotuberculosis infections. In: Coetzer, J.A.W., Tustin, R.C. (Eds.), Infectious Diseases of Livestock, 3rd ed. Oxford University Press Southern Africa, Cape Town, pp. 1917–1930. Paton, M.W., Mercy, A.R., Sutherland, S.S., Ellis, T.M., 1988. The influence of shearing and age on the incidence of caseous lymphadenitis in Australian sheep flocks. Acta Vet. Scand. 84 (Suppl.), 101–103. Paton, M., Rose, I., Hart, R., Sutherland, S., Mercy, A., Ellis, T., 1996. Post-shearing management affects the seroincidence of Corynebacterium pseudotuberculosis infection in sheep flocks. Prev. Vet. Med. 26, 275–284. Paton, M.W., Walker, S.B., Rose, I.R., Watt, G.F., 2003. Prevalence of caseous lymphadenitis and usage of caseous lymphadenitis vaccines in sheep flocks. Aust. Vet. J. 81, 91– 95. Peel, M.M., Palmer, G.G., Stacpoole, A.M., Kerr, T.G., 1997. Human lymphadenitis due to Corynebacterium pseudotuberculosis: report of ten cases from Australia and review. Clin. Infect. Dis. 24, 185–191. Pepin, M., Cannella, D., Fontaine, J.J., Pittet, J.C., Le Pape, A., 1992. Ovine mononuclear phagocytes in-situ: identification by monoclonal antibodies and involvement in experimental pyogranulomas. J. Leukoc. Biol. 51, 188–198. Pepin, M., Fontaine, J.J., Pardon, P., Marly, J., Parodi, A.L., 1991. Histopathology of the early phase during experimental Corynebacterium pseudotuberculosis infection in lambs. Vet. Microbiol. 29, 123–134. Pepin, M., Paton, M., Hodgson, A.L., 1994a. Pathogenesis and epidemiology of Corynebacterium pseudotuberculosis infection in sheep. Curr. Top. Vet. Res. 1, 63–82. Pepin, M., Pittet, J.C., Olivier, M., Gohin, I., 1994b. Cellular composition of Corynebacterium pseudotuberculosis pyogranulomas in sheep. J. Leukoc. Biol. 56, 666–670. Poonacha, K.B., Donahue, J.M., 1995. Abortion in a mare associated with Corynebacterium pseudotuberculosis infection. J. Vet. Diagn. Invest. 7, 563–564. Pre¨ısz, H., Guinard, L., 1891. J. Med. Vet. 16, 563. Purchase, H.D., 1944. An outbreak of ulcerative lymphangitis in cattle caused by Corynebacterium ovis. J. Comp. Pathol. 54, 238– 244. Radostits, O.M., Gay, C.C., Blood, D.C., Hinchcliff, K.W., 2000. Veterinary Medicine, 9th ed. Saunders, London. Robins, R., 1991. Focus on caseous lymphadenitis. State Vet. J. 1, 7–10. Serikawa, S., Ito, S., Hatta, T., Kusakari, N., Senna, K., Sawara, S., Hiramune, T., Kikuchi, N., Yanagawa, R., 1993. Seroepidemiological evidence that shearing wounds are mainly responsible for
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Small Ruminant Research 76 (2008) 42–48
Caseous lymphadenitis夽 M.C. Fontaine a,∗ , G.J. Baird b a
Moredun Research Institute, International Research Centre, Pentlands Science Park, Bush Loan, Penicuik EH26 0PZ, Scotland, UK b SAC Veterinary Services, 5 Bertha Park View, Perth PH1 3FZ, Scotland, UK
Abstract Caseous lymphadenitis has been a prevalent disease among farmed small ruminants in the majority of sheep-rearing countries for over a century. As it is a chronic disease, introduction of control measures in many countries has been slow or absent, resulting in a steady increase in the incidence of the disease. This, in turn, has impacted upon producers with respect to significant economic losses, not to mention issues of animal welfare, through (in extreme cases) chronic ill-thrift, carcase condemnation at abattoirs and reduced wool yields. This short review presents an overview of the current status of research on caseous lymphadenitis, with special reference to transmission of disease, pathology and pathogenesis. © 2008 Elsevier B.V. All rights reserved. Keywords: Sheep; Caseous lymphadenitis; CLA; Corynebacterium pseudotuberculosis
1. Introduction The Gram-positive actinomycete, Corynebacterium pseudotuberculosis, is a cause of chronic infections in a number of different mammalian species, the most significant of which is caseous lymphadenitis (abbreviated either to CLA or CL) of farmed small ruminants. The significance of the disease is evidenced by the scientific research and political debate which has been ongoing in relation to this topic for over a century. Other animal species in which infection with C. pseudotuberculosis is relatively common, include horses (Addo et al., 1974; Miers and Ley, 1980; Poonacha and Donahue, 1995), cattle (Purchase, 1944; Adekeye et al., 1980; Kariuki and Poulton, 1982; Anderson et al., 1990; Shpigel et al., 1993; Yeruham et al., 1997), 夽 This paper is part of the special issue entitled “Current issues in Sheep Health and Welfare guest edited by George C. Fthenakis. ∗ Corresponding author. E-mail address: [email protected] (M.C. Fontaine).
0921-4488/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.smallrumres.2007.12.025
llamas and alpacas (Braga et al., 2006, 2007) and buffalo (Ali and Zaitoun, 1999). In addition, while not as common, C. pseudotuberculosis infection of humans has been reported on several occasions (Lopez et al., 1966; Hamilton et al., 1968; Hill et al., 1978; Henderson, 1979; Keslin et al., 1979; Goldberger et al., 1981; House et al., 1986; Mills et al., 1997; Peel et al., 1997; Join-Lambert et al., 2006), making the disease a potential zoonosis. Following invasion of the host by C. pseudotuberculosis, the organism becomes encapsulated within walled-off lesions from where it evades immune system-mediated destruction, giving rise to a state of persistent infection. This is in contrast to many diseases of veterinary importance characterized by acute and often lethal infections. However, despite the apparent containment of the pathogen within these lesions, the disease is contagious enough to infect the majority of sheep in a flock. 2. Pathogenesis and transmission Infection of small ruminants with C. pseudotuberculosis usually results in the formation of pyogranuloma-
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Fig. 2. Multiple caseous lesions within the lungs. Fig. 1. A ruptured caseous lymphadenitis abscess within the parotid lymph node; there is also loss of overlying hair.
tous lesions (Valli and Parry, 1993), which present in two different ways. The external, also known as cutaneous or superficial, form of CLA is characterized by the development of abscesses within the superficial lymph nodes (Fig. 1) or within the subcutaneous tissue. In either case, abscesses may develop over significant periods of time, becoming swollen and encased within fibrous capsules, resulting finally in the loss of overlying hair and often rupturing (Radostits et al., 2000). Significantly, the purulent contents of ruptured lesions are an important source of cross-infection between animals, since the number of viable organisms contained within pus is between 1 × 106 and 5 × 107 c.f.u./g (Brown and Olander, 1987). Therefore, abscess rupture releases huge numbers of bacteria onto the skin and fleece, resulting in the subsequent contamination of the immediate environment. Neighbouring animals may then be exposed to bacteria, either through direct physical contact with the affected individual or indirectly via contaminated fomites. The second form of CLA manifestation is a visceral form, characterized by the formation of lesions within the animal, which cannot be observed externally. The site of these lesions is commonly the internal lymph nodes (primarily the mediastinal lymph nodes) or lungs (Fig. 2), although other tissues may also be affected. These include primarily the liver, the kidneys or the mammary glands and less frequently the heart, the brain, the spinal cord, the testes, the uterus and the joints (Valli and Parry, 1993). A respiratory route for transfer of C. pseudotuberculosis infection has been postulated (Stoops et al., 1984) and some research suggests that animals with pulmonary lesions may present the major source of exposure to na¨ıve animals within a flock (Ellis et al., 1987; Paton et al., 1988; Pepin et al., 1994; Williamson, 2001). This hypothesis derives from the
observation that lung lesions are not uncommon among infected animals and in some cases appear to be the only site of infection. Pulmonary lesions may be found within the walls of airways, leading to the hypothesis that abscess rupture could result in the production of an infectious aerosol (Stoops et al., 1984; Pepin et al., 1994). In animals with pulmonary abscesses, CLA lesions may also be found within the mediastinal and bronchial lymph nodes, implying migration from the lung parenchyma. Significantly, abscesses within the mediastinal lymph nodes may exert pressure upon the adjacent oesophagus as they grow in size, eventually interfering with normal swallowing and rumination, resulting in chronic ill-thrift (Paton et al., 2005). Although experimental C. pseudotuberculosis infection within the lungs of sheep has been achieved by intratracheal administration of bacteria (Brown and Olander, 1987), more recent studies suggest that pulmonary lesions develop as part of a systemic infection initiated elsewhere in the body. This latter hypothesis would appear to be strengthened by the observation that following experimental inoculation of C. pseudotuberculosis by the intravenous route, the major proportion of internal lesions are found within the lungs and associated thoracic lymph nodes (Brogden et al., 1984). Furthermore, sub-cutaneous inoculation of C. pseudotuberculosis has also been shown to result in formation of multiple infection foci at sites distinct from the initial site of inoculation, including the lungs and mediastinal lymph nodes (Fontaine et al., 2006). In natural cases of CLA, it has been observed that the patterns of distribution of pulmonary lesions are consistent with the theory of haematogenous or lymphogenous spread rather than aerogenous (Nairn and Robertson, 1974). Nevertheless, anecdotal evidence for the aerogenous transmission of C. pseudotuberculosis persists, warranting further research in this area.
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In addition to the intratracheal route described above, sheep have been experimentally infected with C. pseudotuberculosis by inoculation of the organism via the intradermal, subcutaneous, intralymphatic, intravenous, intratracheal and intravaginal routes (Nagy, 1976; Burrell, 1978; Pepin et al., 1994; Fontaine et al., 2006). In naturally observed infections, the main portal of bacterial entry is generally accepted to be through the skin, normally as a result of the presence of minor wounds and abrasions (Batey, 1986b; Brown and Olander, 1987; Davis, 1990; Collett et al., 1994). In many countries, shearing is considered to be a major risk factor in the spread of infection between animals (Nagy, 1976; Paton et al., 1988; Serikawa et al., 1993; Paton et al., 1996; Al Rawashdeh and Al Qudah, 2000), particularly because of wounds that arise during the shearing process and because C. pseudotuberculosis can be transferred on shearing equipment (Paton et al., 1988). If subsequent decontamination measures are inadequate, it is possible that shearing gear, clothing and mobile handling equipment may also serve to transfer infection between flocks. Iatrogenic wounds (as a result of castration and docking) and the umbilicus in neonatal sheep have also been suggested as routes by which C. pseudotuberculosis can gain entry to the host (Valli and Parry, 1993). In addition, head and neck lesions, limited in number in Australian and North American sheep but more frequent in goats, are thought to arise from bacterial entry via the oral cavity (Ashfaq and Campbell, 1979). In the UK, CLA abscesses in sheep tend to be associated primarily with the lymph nodes of the head and neck, which is a similar presentation to that in goats elsewhere in the world (Baird, 2003). However, in small ruminants outwith the UK, the disease primarily affects the superficial lymph nodes of the torso (Nagy, 1971; Ayers, 1977; Stoops et al., 1984; Batey, 1986a; Brown and Olander, 1987; Nuttall, 1988; Muckle and Menzies, 1993; Collett et al., 1994; Williamson, 2001; ChirinoZ´arraga et al., 2006). Based upon what is known of the pathogenesis of CLA, it would therefore seem that the location of superficial lesions is dependent on where the initial point of C. pseudotuberculosis entry occurred, resulting in migration to the local drainage lymph node. In addition to the more frequently encountered manifestations of C. pseudotuberculosis infection described above, the organism may occasionally be the causative agent of mastitis. This condition is most likely to arise as a result of the progression of infection from the supra-mammary lymph node, and may manifest as acute, suppurative mastitis, or alternatively as chronic encapsu-
lated abscesses within the mammary gland. In addition, on rare occasions the organism has also been identified within the stomach contents and tissues of ovine foetuses and has been implicated as a cause of abortion (Dennis and Bamford, 1966). 3. Pathology Following entry into the host through the skin, C. pseudotuberculosis normally migrates to the local drainage lymph node to form microscopic pyogranulomas, which gradually increase in size, eventually combining to form larger abscesses. It has been suggested that carriage within phagocytes is the means by which the organism reaches the lymph node via the lymphatic drainage (Pepin et al., 1994). Dissemination of infection may also occur by transfer of the organism via the blood or lymphatic system and this may result in the formation of lesions at other loci within the host. The ability of the organism to resist immune clearance by the na¨ıve host and disseminate beyond the primary locus of infection is in part due to its ability to survive and replicate within macrophages (Williamson, 2001). Significantly, viable bacteria may routinely be recovered from within abscesses several years following the initial infection and the disease may become “reactivated” as a result of the dissemination of C. pseudotuberculosis after a significant period of apparent dormancy. The host cellular response to infection with C. pseudotuberculosis has been described in detail. In studies involving sheep challenged subcutaneously, vast numbers of neutrophils were shown to be enlisted to the site of inoculation within the first few hours following infection and from there began to move to the local drainage lymph node within 24 h. The importance of neutrophils was found to decrease after 3 days, while the numbers of macrophages at the inoculation site increased significantly (Pepin et al., 1992). A period of generalized inflammation of the lymph node was shown to follow infection and micro-abscesses developed within the cortical region of the node within 24 h of inoculation (Pepin et al., 1991); these became more numerous after approximately 6 days, from which point they began to enlarge and coalesce to form more significant purulent foci. These early pyogranulomas contained clumps of bacteria and cellular debris and a high proportion of eosinophils, giving a characteristic green colour to the purulent material. In addition and concurrently with the cellular response at the site of inoculation, the infiltration of neutrophils declined while monocytes/macrophages became the predominant cell type within the infected
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Fig. 4. Immunohistochemical analysis of the prescapular lymph node shown in Fig. 3, using rabbit anti-C. pseudotuberculosis IgG followed by haematoxylin staining (100× magnification). A zone of coagulative necrosis (A) is present towards the centre of the abscess, followed by a zone of immature fibrosis (B) throughout which bacteria can be visualised as brown dots, laid down in layers along the advancing front of the abscess. A zone of mature fibrosis is observed towards the surface of the abscess (C).
Fig. 3. (a) Transverse histological section of a caseous lymphadenitis lesion within an ovine prescapular lymph node (25 × 22 mm). Multiple concentric layers are discernible within the lymph node: liquifactive necrosis (liquid pus) is observed centrally (A), surrounded by coagulative necrosis (caseous pus; B), both containing multiple foci of mineralization (C); a thin layer of polymorphonuclear neutrophils enveloping the periphery of the coagulative necrosis with a further outer layer of coagulative necrosis containing polymorphonuclear neutrophils migrating through it at different densities and forming an apparent bi-layer (D), bordered by a layer of immature fibrosis delineating the extent of the lesion, in turn bordered by a layer of mature fibrosis (E); some scattered remnants of normal lymph node cortex present peripherally to this (F), surrounded by the thin, fibrous capsule enveloping a normal lymph node (G) (H&E, straight scan 1×). (b) Details of the section in (a) showing the various layers of the lesion. To the extreme right is the presence of liquifactive necrosis (A), followed by extensive coagulative necrosis (B), several foci of mineralization present within the necrotic tissue (dark blue/purple; C), the outer edge
node (Pepin et al., 1994). The lesion became encapsulated shortly afterwards (Fig. 3), resulting finally in a reduction in the inflammatory response within the parenchyma of the lymph node. Once infection has become established, gradual expansion of the lymph node may occur, dependant on its location and whether or not it ruptures to discharge its contents. Lymph node enlargement is brought about through a process of repeated necrosis of the lesion capsule, followed by its reformation. Initially, pus within the abscesses is soft and semi-fluid; however, over time this purulent material becomes more solid and scattered clumps of bacteria may be observed within it (Fig. 4). Small nodules of mineralization form within the purulent material, which cause it to become paler in colour. Additionally, these calcified foci tend to form in concentric layers, giving lesions a lamellated appearance, which is often described as being similar to the cross-sectional view of an onion. This “onion ring” presentation is characteristic in countries, where the disease has been endemic for a significant period of time.
of the necrosis with polymorphonuclear neutrophils (blue dots; D), also present in the immature fibrosis (light pink layer immediately adjacent to the necrotic pink tissue; E); presence of mononuclear inflammatory cells with the surrounding pale pink area being the mature fibrous tissue constituting the capsule of the abscess (F), with what little is left of the normal cortical lymph node tissue seen as aggregations of blue dots (G) and the normal capsule of the lymph node seen as the pale pink material outside this (H) (H&E, 20×).
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4. Distribution Interestingly, while CLA is a significant cause of economic loss and animal welfare problems in some countries, it appears to be relatively insignificant in others (although this may simply be due to under-reporting). Furthermore, while the disease has been resident in some parts of the world since the earliest reports in the late 19th century (e.g., Nocard, 1896; Pre¨ısz and Guinard, 1891), CLA is a new arrival to the United Kingdom, where it was first diagnosed in 1989 following the importation of infected goats (Lloyd et al., 1990; Meldrum, 1990). The disease is prevalent in much of Europe, Africa, the Middle East, Australasia and the Americas (Robins, 1991; Paton et al., 2005) and in many countries the disease has officially been an established problem of sheep for decades. A recent report has provided evidence of a close genotypic relationship between C. pseudotuberculosis isolates of ovine/caprine origin from different parts of the world (Connor et al., 2007), suggesting that the infection may have had a common source and supporting suggestions that the disease was spread around the world through the export of sheep by colonial powers (Paton, 2000). 5. Combating CLA The most efficient way of controlling CLA remains a matter of debate. Vaccination is the primary means of disease control in several countries, whereby immunisation reduces the spread of infection, leading to a gradual decline in disease prevalence. That said, no proprietary CLA vaccine currently available offers complete protection against infection by C. pseudotuberculosis; hence, the disease will continue to manifest, albeit at reduced level. This is evidenced by a report from Australia which indicated that, despite the widespread use of a commercial CLA vaccine in that country since 1983, disease prevalence remained at approximately 20% in 2002 (Paton et al., 2003). As an alternative to vaccination, serological diagnosis offers a powerful means of combating disease, through the culling/segregation of infected animals. This approach, while potentially costly in the first instance, is a means by which CLA may be completely eradicated from affected flocks. However, it is likely only to be of practical use in flocks that do not have a high incidence of the disease, given that the majority of farmers would not willingly relinquish the major portion of their animals. Therefore, it seems that a marriage of vaccination and serodiagnosis would provide the flexibility required for control of CLA. In this respect the continued develop-
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