Michele L. Frazer
Lawsonia intracellularis Infection and Proliferative Enteropathy
Proliferative enteropathy caused by Lawsonia intracellularis historically has been considered a disease of pigs, but in the past decade L intracellularis has emerged as an important equine pathogen. First described as proliferative enteropathy (PE) in a pig in 1931, the disease manifested as two unique syndromes that were differentiated by the presence or absence of intestinal hemorrhage. Although a Campylobacter species was consistently isolated from many cases of porcine PE, it was not usually found in those with intestinal hemorrhage. In the 1980s, Scottish veterinarian Gordon Lawson confirmed that the causative organism was not Campylobacter, and the organism was referred to as campylobacter-like organism or intracellular organism. In recognition of Dr. Lawson’s research, the organism was named Lawsonia intracellularis in 1995.
In the horse, PE was first described in 1982. Several case reports in the 1990s described intestinal lesions similar to those in the pig, suggesting that the same organism was involved in both species. In 1996, the causative organism of equine proliferative enteropathy (EPE) was identified as Lawsonia intracellularis. Since then, the disease has been reported in North and South America, Europe, and Australia. Lawsonia intracellularis, typical histopathologic changes of PE, or both have now been identified in many species, including the horse, pig, raccoon, hamster, rat, mouse, rabbit, emu, ostrich, monkey, sheep, white-tailed deer, dog, cat, fox, ferret, and guinea pig in nonhuman primates.
Pathophysiology
Lawsonia intracellularis is an obligate, intracellular, gram-negative, curved-rod–shaped, non–spore-forming bacteria. Lesions usually start in the lower ileum and sometimes the large intestine. Edema develops in the serosal layer and results in accumulation of necrotic material and a thickened mucosa. Crypt cells expand and elongate, and the bacteria are usually seen in the apical portion of the cytoplasm of infected cells. Mitotic cells are abundant, whereas inflammatory cells and goblet cells are reduced or absent. The junction between normal and abnormal tissue is clearly demarcated, and the areas usually involve the epithelial layer and not the lamina propria or muscularis mucosae, although involvement of the latter may occasionally occur. Older animals are more likely to have hemorrhagic PE, as opposed to those of weaning age. In hemorrhagic cases, the mucosal thickening is not as apparent, congestion of the mucosal blood vessels occurs, and inflammatory cells are present in the lamina propria.
As in the pig, L intracellularis in the horse affects the crypt cells. This causes increased mitosis and thus ileal mucosal hyperplasia. However, the hyperplastic cells lack a functional brush border, which eventually leads to intestinal malabsorption and the associated clinical findings.
The primary exposure source of the disease in pigs is mixing of chronic carriers with naïve pigs. In horses, the primary source of the organism in the environment is still largely unknown. Recent studies have suggested that the cat, mouse, and rabbit could be either reservoir or amplifying hosts. Transmission between horses is likely, through the fecal-oral route. Unlike the pig and the hamster, isolated clinical cases occur in the horse in addition to herd outbreaks.
Clinical Syndrome
Lawsonia intracellularis most commonly affects foals and weanlings younger than 6 to 7 months. The decrease in maternal antibody titer, as well as the stress of procedures such as weaning, vaccinations, deworming, and training that are performed in weanlings, may contribute to increased incidence in this age group. Horses typically first exhibit clinical signs of disease in late fall and early winter, the time of year when many horses reach 6 to 7 months of age, although environmental and other seasonal factors cannot be ruled out. A sex or breed predilection has not been established.
The most consistent clinical sign in horses with L intracellularis infection is ventral edema, which develops in 81% of affected animals. The ventral edema can range from mild (slight swelling in the throatlatch or pectoral area) to severe, which can lead to rupture of the integument and serous or purulent drainage from the pectoral, abdominal, or scrotal areas. Horses may have respiratory distress consequent to severe edema in the throatlatch area.
Mild to severe diarrhea is reported to occur in 26% of infected horses. In mild cases, dehydration may not be seen, but severe cases present with profound dehydration, electrolyte and acid-base derangements, and azotemia. Other clinical signs include weight loss, fever, lethargy, colic, rough haircoat, pot-belly appearance, and poor body condition.
Laboratory Values
Hypoproteinemia, specifically hypoalbuminemia, is a consistent clinicopathologic finding with L intracellularis infection. Other abnormalities include hyperfibrinogenemia, toxic neutrophils with a left shift, azotemia, metabolic acidosis, and high creatine kinase, although these findings are variable.
Diagnosis
Polymerase chain reaction can be used to identify the organism in a fecal sample or, if fecal production is decreased and a sample is not available, from a rectal swab. False-negative results may occur if the horse had already received antimicrobials before sampling and DNA is no longer present. A positive result indicates the presence of L intracellularis DNA, but does not confirm active infection, so this information should be combined with clinical presentation to establish a diagnosis.
Serology using immunoperoxidase monolayer assay confirms the presence of antibodies and may be a more reliable indicator of active or recent infection. False-negative results may occur if the horse fails to mount an appropriate immune response. Also, the duration of titer is unknown. Therefore, if only one sample is taken, misdiagnosis is possible because the horse may have had a high titer initially but have a declining titer by the time the blood sample is taken.
The gold standard diagnostic test is use of the Warthin-Starry silver stain to reveal the organism in intestinal tissue taken at postmortem or from intestinal biopsy during exploratory laparotomy. Intestinal mucosa obtained from a duodenal biopsy specimen (obtained through gastric endoscopy) or a rectal biopsy does not typically harbor the organism, even when the latter is present in the ileum, jejunum, or colon.
Other, less useful diagnostic modalities include electron microscopy and fecal culture. Although the organism can be detected by electron microscopy, most laboratories do not have this capability, and it is not practical on an antemortem basis. Growth of the organism from a fecal sample on culture media is difficult and not routinely performed because the organism requires cell cultures of enterocytes for replication.
Abdominal ultrasound is useful in suggesting a diagnosis of L intracellularis infection. Hyperplasia of the intestine often causes a grossly thickened small intestine wall, colon wall, or both. Mural thickness greater than 3 to 4 mm in the small intestine and 4 to 5 mm in the colon is consistent with intestinal thickening.
Presumptive diagnosis is often made on the basis of clinical signs, abdominal ultrasound findings, and exclusion of other differential diagnoses for hypoalbuminemia. This allows for early initiation of treatment while waiting for laboratory confirmation and may result in a better outcome for the horse. Other differential diagnoses for the typical clinical signs seen with L intracellularis infection and hypoproteinemia in foals and weanlings include parasitism (e.g., ascarids, strongyles, and encysted cyathostomes), infectious agents (Salmonella spp, Clostridium spp, and rotavirus), and inflammatory bowel disease. Less common causes include intestinal ulcers, liver disease, glomerular disease, Rhodococcus spp infection, and severe malnutrition. Initial baseline diagnostics for a weanling with hypoalbuminemia or hypoproteinemia and clinical signs consistent with L intracellularis infection should include testing of feces for Salmonella, rotavirus, possibly Clostridium, and parasites, as well as testing of serum and feces for L intracellularis.
