Proliferative enteropathy, also known as PE or ileitis is a common enteric disease affecting pigs raised under various management systems world-wide.
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Ileitis & Lawsonia intracellularis

what do we know today?

by
STEVEN MCORIST - Tufts University College of Veterinary Medicine
SIONAGH H. SMITH - University of Pennsylvania
ALISON M. COLLINS - University of Sydney

Reproduced by kind permission of the "Swine Disease Conference for Swine Practitioners"
Iowa State University, U.S.A.

*Introduction   *References
 
*New Diagnostic Tools & Targeted Medication Programs
 
*Development of Ileitis Vaccines   *Eradication Programs


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Introduction

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The causative agent of proliferative enteropathy is Lawsonia intracellularis, a Gram negative obligate intracellular bacterium in the Desulfovibrio family.1,2 Infection of pigs with this bacterium is consistently linked with the presence of proliferative lesions of the mucosa of the ileum and large intestine, hyperplasia of crypt enterocytes along with a decrease in goblet cells in association with the presence of intracellular, curved or S-shaped Lawsonia bacteria.

  The chronic forms of PE lead to clinical or sub-clinical effects on weight gain, feed conversion and fecal consistency. Clinical observations generally include diarrhea, with "variation" in the weights of growing pigs.3 It also may present as an acute form with sudden death or bloody diarrhea due to massive hemorrhage within infected proliferative mucosa, particularly in late finishing pigs and replacement gilts. Since the fulfillment of Kochs' postulates in 1993 and identification of the antibiotic sensitivity of the organism in 1995, the major areas of ileitis research in the past few years have focused on i/ combining new diagnostic tools with targeted medication programs, ii/ developing vaccines and iii/ developing information necessary for potential eradication programs. Other work has focused on the bacterium itself, with aspects such as pathogenesis and taxonomy, but these are not considered here.

 

 

New Diagnostic Tools & Targeted Medication Programmes

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The range of antibiotics that are truly useful against Lawsonia intracellularis was first suggested by laboratory studies in 1995, now verified by numerous challenge-exposure studies, in groups with and without test antibiotics. The range of antibiotics that is efficacious at suitable and sufficient dose rates on a bodyweight basis includes macrolides, pleuromutilins, lincosamides and tetracyclines. All these compounds have a similar mode of action against the ribosomes of Gram negative bacteria. Products which show poor intracellular activity or are active against Gram positive bacteria or against the cell wall of bacteria show less or no activity and are not recommended.4 This firstly emphasizes the importance of accurate diagnosis before medication programs are commenced. Diagnosis has traditionally relied on necropsy of clinically affected stock, but new ante-mortem methods are now available, such as serology and PCR. Practical combinations of the new diagnostic methods and various medication strategies are now starting to be reported.

  Recent experimental studies have now indicated that continuous medication, particularly at high doses during the grower period, tends to reduce the level of immunity to PE as measured by serology responses to challenge and by susceptibility to re-challenge. In one study, 10 pigs were maintained on 250 ppm of oxytetracycline for 12 weeks, from 6 to 18 weeks-old, then challenged orally with Lawsonia intracellularis. Two pigs developed clinical signs of acute haemorrhagic PE, 2-3 weeks after challenge, with bloody feces evident. All 10 challenged pigs showed gross and histologic lesions of PE and developed serologic responses only after challenge.5 Similarly, in a recent study of pigs challenged with L intracellularis and also given high doses of pleuromutilin water medication, the percentage of pigs with an active immune response was reduced.6 Also in a third study, groups of pigs were challenged with L intracellularis, and given 400ppm chlortetracycline in-feed from 4 days prior, to 31 days after challenge, with relevant unmedicated controls. The medicated pigs showed no evidence of L intracellularis infection when monitored for fecal shedding or serum antibodies between 0 and 28 days after challenge. The pigs were re-challenged at 35 days after challenge, with L intracellularis. Positive fecal PCR and serology was quickly detected in 4 of 5 re-challenged pigs infection over the next 2-3 weeks.7 It is therefore likely that continuous levels of anti-Lawsonia antibiotics supplied to pigs prior to exposure can prevent infection, but, importantly, can also prevent development of immunity and extend susceptibility to infection.

  A further suggestion has been the advocacy of antibiotics at low levels of likely efficacy, to allow possible breakthrough of infection and immunity, but with some control of clinical signs. To test this, a further group of pigs was medicated continuously with 25ppm olaquindox in-feed from -4 to 31 days after the L intracellularis challenge at day 0 (3 weeks-old), with relevant unmedicated controls.7 These pigs varied greatly in their susceptibility to infection following both this first challenge and a second L intracellularis challenge 5 weeks after the first one. Low levels of olaquindox in-feed before initial exposure to L intracellularis did not prevent infection in all pigs and appeared to delay infection in some pigs. Some pigs maintained on low levels of olaquindox in-feed did not become infected with L intracellularis after initial exposure and therefore did not develop immunity to L intracellularis infection. Three of six pigs shed detectable numbers of L intracellularis in their feces, with reductions in average weekly weight gains evident 3 weeks after re-challenge. We therefore concluded that these minimalist strategies are bound to be unreliable for control.

  Broad continuous medication programs are therefore no longer considered useful for on-going control of PE. They may even give the illusion of acquired resistance to the antibiotic in use. Targeted medication programs are seen as not only the most cost-effective, but also the most active way to use antibiotics. However, efficient use of targeted meducation programs relies on a knowledge of the epidemiology of PE in farms. Many farms have now been studied with respect to their PE serology profile in relation to disease patterns. A summary would be that a typical pattern is a very low number of positive reactors or excretors in the boars, dry and pregnant sows, farrowing sows and new-born piglets. Many young piglets have some detectable maternal antibody transfer, but this declines at around 3-5 weeks-old. On most farms studied, a rapid rise in the numbers of positive reactors and excretors is detected at some point in the grower-finisher cycle, often around 12-18 weeks-old.8,9 This time can change between farms and between batches on the same farm, but is usually seen within this broad range. It is considered likely that the organism is cycling in the unit prior to the "break", with infection building over each 2-3 incubation period until sufficient shedders occur to enable rapid spread.

  A further aim would therefore be to examine the time of the "break" of serology/infection on farms, combined with a targeted medication program, just after the occurrence of infection. This should lead to reduction of clinical signs without compromise of possible immunity development. This combination of monitoring the response of the pig via diagnostic assays and the use of medication programs in controlled on-farm medication studies has now been reported, with in-feed tylosin and lincomycin-spectinomycin in water both showing good activity in two respective studies.10,11 However, many more on-farm studies are required. In one experimental study, we established pig groups that were inoculated orally with L intracellularis at 3 weeks-old, then treated with 400ppm in-feed chlortetracycline from 14 to 24 days after the first challenge, then re-challenged at 7 to 8 weeks-old, with relevant controls at each stage.7 All the medicated re-challenged pigs developed serum IgG antibodies to L.intracellularis of varying intensity from 28 to 70 days after re-challenge. Following re-challenge, the pigs did not shed detectable levels of L.intracellularis in feces, but did develop a secondary serum IgG response. Clinical signs of disease including diarrhea and reduced weight gains were only observed in challenged, unmedicated control pigs, with fecal shedding of L intracellularis DNA detected 2-3 weeks after challenge. It was concluded that medication programs commenced after exposure are more likely to lead to specific therapy and immunity. Other groups of challenged pigs medicated with various other regimens of chlortetracycline or olaquindox are mentioned above, which showed less consistent control patterns. It is likely that medication programs need to be tightly related to exposure times, for groups of pigs to be fully resistant to re-challenge.

 

 

Development of Ileitis Vaccines

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Considering the possible questions over antibiotic usage, as well as their costs, both monetary and socio-political, the development of ileitis vaccines has been examined by several international companies. While enteric vaccines, such as for Brachyspira spp, have generally had a poor record in pigs, the concept of an ileitis vaccine has some support. Firstly, the development of immunity to L intracellularis has been demonstrated during sequential natural outbreaks of acute hemorrhagic PE.12 An initial outbreak affected breeding sows and boars of all ages, which was controlled with antibiotics. A second episode two to three weeks later, affected only gilts and young boars introduced into the breeding unit after the first L intracellularis infection period had ceased, with pigs that were previously exposed, being immune to infection during the second episode. Secondly, Lawsonia have been consistently demonstrated in intestinal macrophages in deeper parts of the mucosa, and occasionally in lymph nodes, indicating the pig has adequate immunologic cellular exposure to the bacterium. Thirdly, initial experimental re-challenge studies have indicated that following re-challenge, pigs did not shed detectable levels of L intracellularis in feces, but did develop a secondary serum IgG response.7

  One US company has recently developed an avirulent isolate of Lawsonia intracellularis using a patented method of cultivation and attenuation. They have now reported proof of the concept of vaccination for ileitis in experimental challenge studies following vaccination with this avirulent NP40 strain delivered in water or intranasally.13 In one study, groups of pigs received different intranasal doses with a 2 ml volume of the L. intracellularis vaccine strain, or remained unvaccinated. Twenty-eight days after vaccination all pigs received a virulent pure culture challenge of L intracellularis. Gross and microscopic lesions typical of PPE were significantly more prevalent in challenge control pigs compared to vaccinated pigs (PŁ0.05), with 33 of 34 pigs in the vaccinates showing no lesions. This study was the first to demonstrate the effectiveness of an avirulent L. intracellularis isolate in reducing lesion development, fecal shedding and productivity losses associated with PE in pigs. In further studies, use of the avirulent L. intracellularis isolate in a water delivery system similar to that used to deliver Salmonella vaccines was evaluated in vaccinates and challenge controls. The vaccine was administered at weaning for 4 hours in the drinking water, stabilized with sodium thiosulfate. Following virulent challenge 7 weeks after vaccination, the pigs were monitored and necropsied 3 weeks later. Again, there was a significant reduction in PE lesions in vaccinates and one challenge control died from acute PE following the challenge. On-farm trials and further research into aspects such as maternal antibody effects are continuing. Other companies have patented parts of the Lawsonia genome and may develop other potential vaccine strategies.

 

 

Developing Information Necessary
for

Potential Eradication Programs

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Field and challenge-exposure studies indicate that Lawsonia infection may persist in some pigs for at least 10 weeks, with numerous organisms being passed in the feces.14 Grower-finisher pigs as well as any L intracellularis-infected breeding stock, may play an important role in transmission to younger susceptible animals, via infected feces. Preliminary pen exposure studies have evaluated infection in sentinel pigs in contact with challenged pigs and in one study, transmission occurred despite the use of routine cleaning procedures between pens.15 Inoculation of potential on-farm animal vectors of L intracellularis, such as mice or rats, has produced conflicting results. One study indicated that these may play only a minor role in transmission of the disease, but in other studies infected rats and mice were thought to be capable of carrying and excreting porcine L intracellularis.

  The efficacy of various disinfectants against L intracellularis, as indicated by subsequent co-culture of the organism was evaluated in a recent study.16 Mixing of cetrimide (3.3% w/v final concentration) with suspensions of L intracellularis, resulted in no detectable organisms remaining. Mixing of povidone-iodine with L intracellularis did result in complete or marked reduction of detectable bacteria (< 1% of controls) on subsequent re-culture. The acidic oxidizing agent, hydrogen peroxide/peracetic acid and the chlorine-releasing agent, sodium hypochlorite considerably damaged the in vitro system used, despite a washing procedure. A reduced dose of sodium hypochlorite still led to no detectable bacteria on re-culture of one strain. Formalin or glutaraldehyde based compounds were not tested. Viable L intracellularis were detectable up to 8 days in suspensions kept in culture medium in plastic vessels (without cells or chemicals) in air at 5C, but for only one or 2 days when kept at higher temperatures.

  In further studies,16 feces were collected from an adult pig naturally infected with L intracellularis and stored in an open plastic container at 10C. Portions of feces were harvested at day 0, then one, 2 or 4 weeks after collection and used as an oral inoculum for challenge-exposure of weaned pigs. Four of five pigs challenged on day 0 with fresh feces, developed moderate to severe diarrhea and reduced weight gains compared to non-challenged littermates. One of five pigs challenged with one-week old feces developed diarrhea from 28 days after challenge, but no other pigs showed diarrhea. PCR products consistent with Lawsonia intracellularis DNA were amplified from control DNA material and from the feces of pigs challenged with feces of 0, 1 or 2 weeks storage, but not from pigs challenged with samples from 4 weeks storage. Similarly, serum IgG antibodies to L intracellularis were detected from 21 days after challenge in pigs challenged with feces of 0, 1 or 2 weeks storage, but not in control pigs nor in pigs challenged with samples from 4 weeks storage.

  The results suggest that Lawsonia intracellularis may be viable outside the host for at least two weeks under certain conditions. The possibility that fecal contamination of pens, troughs and equipment could lead to a continuing cycle of infection among new pigs, with subsequent shedding of organisms in the feces of in-contact pigs, offers a problematic view for potential control. Previous challenge studies have indicated that only a moderate challenge inoculum (106-108 organisms) is required to initiate pathogenic intestinal infection and persistent fecal shedding can occur.2,14 The results further emphasize that spread of infection among groups of pigs in a single building or farm could be rapid and far-reaching, without adequate biosecurity.

  Although effective antibiotics and possible on-farm medication programs are now known, eradication of proliferative enteropathy by medication and livestock control procedures has not been described. Full biosecurity may only be achieved where pens are cleaned and rested for 2 weeks and incoming pigs are known to be free of infection. Whole bacterial vaccines are now in active use in on-farm trials, with apparently good efficacy comparable with other "production" vaccines and these may prove a better long-term control method in many situations.

 

 

References

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1. McOrist S, Gebhart CJ, Boid R. et al 1995. Characterization of Lawsonia intracellularis gen. nov., sp. nov., the obligately intracellular bacterium of porcine proliferative enteropathy. Int. J. Syst. Bacteriol. 45: 820-825.

2. McOrist S, Jasni S, Mackie RA et al 1993. Reproduction of porcine proliferative enteropathy with pure cultures of ileal symbiont intracellularis. Infect. Immun. 61: 4286-4292.

3. Winkelman N 1996. Ileitis: an update. Comp. Contin. Educ. 18, S19-S25.

4. McOrist S, Gebhart CJ 1995. In vitro testing of antimicrobial agents for proliferative enteropathy (ileitis). Swine Health Prod. 3, 146-149.

5. Collins AM, McOrist S, van Dijk M et al 1999. The effect of age on clinical disease associated with Lawsonia intracellularis infection. Proc. 7th Conf. Aust. Pig Science Assoc., Adelaide, Australia, p 277.

6. Walter D, Knittel J, Schwartz K et al 2000. Effectiveness of tiamulin in the drinking water for treatment and control of porcine proliferative enteropathy (ileitis) due to Lawsonia intracellularis infection. Proc IPVS. 16, 31.

7. Collins AM, van Dijk M, McOrist S et al 2000. Strategic medication and development of immunity to Lawsonia intracellularis. Proc IPVS. 16, 30

8. Philips RC, Geiger JO, Karhoff K 1998. Evaluation of the use of Lawsonia intracellularis indirect fluorescent antibody test (IFA) in a large production system. Proc AD Leman Conf. p5-6.

9. Lopez J, Rodriguez J, Valle R et al 2000. A longitudinal study of porcine proliferative enteropathy in a commercial pig farm in Yucatan, Mexico. Proc IPVS. 16, 68

10. McOrist S, Smith SH, Klein T 1999. Monitored control programme for proliferative enteropathy on British pig farms. Vet. Rec. 144, 202-204.

11. McOrist S, Muller Wager A, Kratzer D et al 2000. Therapeutic efficacy of water-soluble lincomycin-spectinomycin powder against porcine proliferative enteropathy in a European field study. Vet. Rec. 146, 61-65.

12. Love RJ, Love DN, Edwards MJ  1977. Proliferative haemorrhagic enteropathy in pigs. Vet.Rec. 100, 65-68.

13. Knittel J, Kroll J, Mathes M et al. 2000. Efficacy of an avirulent Lawsonia intracellularis vaccine in swine. Proc IPVS. 16, 24

14. Smith SH, McOrist S 1997. Development of persistent intestinal infection and excretion of Lawsonia intracellularis by piglets. Res. Vet. Sci. 62: 6-10.

15. Winkelman NL, Pauling GE, Bagg RN et al 1998. Use of a challenge model to measure the impact of subclinical porcine proliferative enteritis on growth performance in pigs. Proc AASP. 29, 209-211.

16. Collins AM, Love RJ, Pozo J et al 2000. Studies on the ex vivo survival of Lawsonia intracellularis. Swine Health Prod. 8, 211-215.

 

 

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