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LEPTOSPIROSIS VIRUS OVERVIEW

An Overview of Canine Leptospirosis

Richard Noel, DVM; Kenneth S. Latimer, DVM, PhD

Class of 2000, University of the West Indies, School of Veterinary Medicine, Trinidad (Noel) and Department of Pathology (Latimer), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

Leptospirosis is a zoonotic disease of worldwide veterinary significance in many animal species. It is caused by infection with antigenically distinct serovars of the spirochete Leptospira interrogans sensu lato, of which eight are of greatest importance to dogs and cats (Fig. 1). The genus has been classified into new species on the basis of genetic relatedness.1 On the basis of serologic relatedness, as determined by cross-agglutination and agglutinin-absorption tests, these species are further divided into several serogroups (e.g., Leptospira canicola, L. icterohaemorrhagiae and L. pomona). There are multiple, antigenically distinct organisms within each serogroup, which are referred to as serovars.9 Serovars are maintained in nature in numerous subclinically infected wild and domestic animal reservoir hosts that serve as potential sources of infection and illness for humans and other incidental hosts.1 The preferred reservoir host and likely incidental host vary with the serovar as well as the geographic location.4 Leptospira sp. cannot replicate outside of a host.6

Figure 1. Scanning electron micrograph of Leptospira spp. Notice the corkscrew appearance of the bacterium (Courtesy of Noah's Arkive, The University of Georgia).

Several antigenically distinct serovars of L. interrogans sensu lato or L. kirschneri are responsible for disease in dogs. The serovars most commonly incriminated in canine infection and their common reservoirs include L. canicola (dog), L. icterohaemorrhagiae (rodents), L. gryppotyphosa (raccoon, skunk, opossum, vole), L. pomona (cattle, swine, skunks, opossum), and L. bratislava (rodents, swine).3

Leptospirosis has a seasonal distribution and is most prevalent in late summer to fall. Rainfall can be used to predict the occurrence of leptospirosis.2

Pathogenesis

The animal host acts as a reservoir, shedding the bacterium intermittently.5 Leptospires (the organism) are passed in urine and penetrate mucous membranes or abraded skin and multiply rapidly upon entering the blood vascular space. The bacterium continues to spread within the body and replicates further in many tissues including the kidney, liver, spleen, central nervous system (CNS), eyes, and genital tract (Figs 2 and 3). Thereafter, increases in serum antibodies clear the spirochetes from most organs, but bacteria may persist in the kidneys and be shed in urine for weeks to months. The extent of damage to internal organs is variable depending on the virulence of the organism and host susceptibility.1

Figure 2. Liver of a dog that died of leptospirosis. Multifocal hepatic necrosis is associated with a mottled appearance of this organ (Courtesy of Noah's Arkive, The University of Georgia). Figure 3. Kidney of a dog that died of leptospirosis. Multifocal interstitial nephritis and renal tubular necrosis are associated with a spotted appearance of the renal parenchyma (Courtesy of Noah's Arkive, The University of Georgia).

Different serovars have a propensity to produce clinical disease with particular characteristics; renal, hepatic, and vascular disease are of greatest importance.3 Hepatic dysfunction usually is associated with the serogroups icterohaemorrhagiae and pomona, while subacute nephritis is associated with the serogroups canicola and gryppotyphosa; however. However, all of these serovars of Leptospira can produce hepatic or renal failure. For example, dogs that recover from acute hepatic disease may succumb to renal failure from nephritis.9,1 Younger dogs (< 6 months) seem to develop more signs of hepatic dysfunction in an outbreak of leptospirosis; however, acute renal failure in young dogs is often associated with L. grippotyphosa.1 More than one form of leptospirosis may occur in a given animal, and the clinical manifestations can vary among outbreaks and geographic areas with a given serovar.

Tissue edema and disseminated intravascular coagulation (DIC) may occur in rapid and severe leptospirosis that results in acute endothelial injury and hemorrhage (Fig. 4). Leptospira lipopolysaccharide stimulates neutrophil adherence and platelet activation, which may precipitate inflammatory and coagulation abnormalities.1

Figure 4. Lungs of a dog that died of leptospirosis. Multifocal hemorrhage is apparent, suggesting possible disseminated intravascular coagulation (Courtesy of Noah's Arkive, The University of Georgia).

The liver is the second major parenchymous organ damaged during leptospiremia. Profound hepatic dysfunction may occur without major histologic changes because of subcellular damage produced by leptospiral toxins. The degree of icterus in both canine and human leptospirosis usually corresponds to the severity of hepatic necrosis.1

Chronic active hepatitis has been a sequela to serovar gryppotyphosa infection in dogs. Presumably, initial hepatocellular injury and persistence of the organism in the liver result in altered hepatic circulation, fibrosis, and immunologic disturbances that perpetuate the chronic inflammatory response. Extensive hepatic fibrosis and hepatic failure may result from this process. Other body systems, (e.g. CNS) also are damaged during the acute phase of leptospirosis.1

Clinical Signs

The clinical signs of canine leptospirosis depend on the age and immunity of the host, environmental factors affecting the bacteria, and the virulence of the infecting serovar. Young animals are more severely affected than adults.

Peracute Infection - Peracute leptospirosis can be associated with massive leptospiremia. Death may occur rapidly with few premonitory signs.

Subacute Infections - Subacute infections are characterized by fever, anorexia, vomiting, dehydration, and increased thirst. Reluctance to move and paraspinal hyperesthesia in dogs may result from muscular, meningeal, or renal inflammation. Mucous membranes appear injected, and petechial and ecchymotic hemorrhages are widespread. Progressive deterioration in renal function is manifested by oliguria or anuria. In some dogs surviving subacute leptospirosis, renal function may return to normal within 2 to 3 weeks or chronic, compensated, polyuric renal failure may develop.1

Acute Infections - Pyrexia (103-104°F), shivering, and generalized muscle tenderness are the first clinical signs in acute leptospirosis. Vomiting, rapid dehydration, and peripheral vascular collapse subsequently, occur. Coagulation defects and vascular injury are characterized by hematemesis, hematochezia, melena, epistaxis, and widespread petechiae.1 Icterus is common in dogs affected with the acute form of disease. Intrahepatic cholestasis from hepatic inflammation may be so complete that fecal color changes from brown to gray. Dogs with chronic active hepatitis or chronic hepatic fibrosis as a sequela to leptospirosis, may eventually demonstrate overt signs of liver failure, including chronic inappetance, weight loss, ascities, icterus, or hepatoencephalopathy.1

Chronic / Subclinical Infections - A majority of leptospiral infections in dogs are chronic or subclinical. Serologic and microbiologic evaluation for leptospirosis should be performed on dogs with fever of unknown origin, unexplained renal or hepatic disease, anterior uveitis, on healthy dogs in kennels, multidog households, and neighborhoods or other environments where infection in other dogs has been documented.

Clinical Laboratory Findings

Many dogs with leptospirosis develop azotemia due to acute renal failure.3 Hematologic findings in typical cases of canine leptospirosis include leukocytosis and thrombocytopenia.1 Anemia has been reported to be a clinical feature of this disease, but this laboratory finding seems to be dependent on the degree of toxemia.7 Leukocyte counts fluctuate depending on the stage and severity of infection. Leukopenia is common in the leptospiremic phase, but transitions into leukocytosis with a left shift. A majority of dogs with leptospirosis have renal failure on initial examination. 1 Thrombocytopenia and increased fibrinogen degradation products have been found in dogs with experimental infection with serovar L. icterohaemorrhagiae. However, other hemostasis parameters are within the reference interval in most dogs, suggesting compensated hemostatic mechanisms. Severely affected dogs frequently have vascular endothelial damage with hypofibrinogenemia and thrombocytopenia resulting from DIC. 1

Increased serum urea and creatinine concentrations are found in dogs with variable severity of renal failure. Electrolyte alterations usually parallel the degree of renal and gastrointestinal dysfunction. Hyponatremia, hypochloremia, hypokalemia, and hyperphosphatemia are usually present, whereas hyperkalemia and hypoglycemia may develop in dogs with terminal renal failure. Mild hypocalcemia is related to hypoalbuminemia and decreased concentration of the protein-bound calcium fraction. Hypoglycemia is occasionally present with severe hepatic failure. 1

Hepatic dysfunction may be apparent in some dogs, but it usually is less dramatic than renal failure or is associated with concurrent renal failure. Liver damage is demonstrated by increased serum alanine aminotransferase (ALT), aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase (ALP) activities. Bilirubin concentration also is increased, reflecting cholestasis. The increase in serum ALP activity often is proportionally greater than that of ALT activity. Increased serum amylase and lipase activities may result from their release from inflamed hepatic and small intestinal tissues and from decreased renal clearance.1

Dipstick alterations on urinalysis can include glucosuria, tubular proteinuria, and bilirubinuria. Microscopic examination of the urine sediment may reveal increased numbers of granular casts, leukocytes, and erythrocytes. Leptospires will not be observed on microscopic examination of the sediment without special staining or dark-field microscopy.

Diagnosis

Diagnosis of leptospirosis is based on a combination of suggestive historical information, physical findings, nonspecific laboratory findings, and confirmatory testing. Often, serovars canicola and gryppotyphosa are described in association with renal dysfunction and minimal hepatic disease, while serovars icterohaemorrhagiae and pomona produce both hepatic and renal damage. Realistically, the clinical disease is similar enough that the serovar resulting in infection cannot be distinguished without confirmatory testing. Any serovar is capable of producing endothelial damage, vasculitis, and acute complications including DIC and edema.3

Confirmatory tests include serologic testing to detect antibody production to leptospira. Very high antibody titers are suggestive of infection, but paired serum titers produce more reliable prognostic information. Direct detection of the bacterium may be done by culture of urine or blood culture, polymerase chain reaction (PCR) identification of leptospiral DNA, FA staining of urine, or urine dark-field microscopy.3 Culture of Leptospira spp. can be difficult. Sometimes a reference laboratory may have to be employed for specific identification of the bacterium, especially when a new serovar is suspected.10 If the patient has been treated with antibiotics prior to collection of laboratory specimens for analysis, the number of bacteria in urine and blood may decrease in number rapidly. In such circumstances, the diagnostic tests listed above may be negative because of poor sensitivity.3

In formal fixed, paraffin embedded necropsy tissue specimens, purulolymphoplasmacytic tubulointerstital nephritis may be observed (Fig. 5). Organisms often are inapparent in hematoxylin and eosin-stained tissue specimens; however, Leptospira spp. can be visualized microscopically following silver (Fig. 6) or immunohistochemical staining (Fig. 7).

Figure 5. Purulolymphoplasmacytic tubulointerstital nephritis in a dog that died of leptospirosis. (Hematoxylin and eosin stain, courtesy of Noah's Arkive, The University of Georgia).

 

Figure 6. Spirochetes of Leptospira sp. appear as black threads within the lumina or renal tubules (van Orden stain, courtesy of Noah's Arkive, The University of Georgia). Figure 7. Spirochetes of Leptospira sp. stain red-brown along the lumenal walls of renal tubules (immunoperoxidase stain, courtesy of Noah's Arkive, The University of Georgia).

Management and Treatment

Note: Treatment of animals should only be performed by a licensed veterinarian. Veterinarians should consult the current literature and current pharmacological formularies before initiating any treatment protocol.

Fluid Therapy - Fluid therapy is the cornerstone of the management of patients with leptospirosis. Patients presenting in shock should be treated with aggressive intravenous fluids and dehydration should be corrected over 6-24 hours.2 Fluid therapy should be continued at diuretic levels once dehydration is corrected. It may be necessary to measure the fluid administered and urine output if polyuria or oliguria is suspected. In any event, the urine produced by a patient suspected of having leptospirosis should be collected and considered a biological hazard.

Antiemetics - Vomiting is frequently severe with leptospirosis, and antiemetics (metoclopramide, chlorpromazine, ondansetron) may be necessary.

Antibiotic Therapy - Penicillin and its derivatives (e.g., ampicillin) and doxycycline are very effective in eliminating the leptospiremic phase of disease. These drugs are an excellent choice for initial treatment. However, the penicillins do not eliminate the carrier state of leptospirosis. Tetracyclines, fluroquinolones, and erythromycin will eliminate the carrier state of disease, but antibiotic treatment should be continued for at least 4 weeks.3,4

Patient survival rates as high as 80-90% have been reported in dogs following either traditional medical management or medical treatment with concurrent hemodialysis. Possible long-term outcomes of leptospirosis include complete clinical recovery, chronic renal failure, and chronic active hepatitis.

Immunization

Leptospira spp. bacterins are serovar-specific. For over two decades, typical bacterins were designed to protect dogs from L. canicola and L. icterohaemorrhagiae. However, these products did not provide protection from infection by other serovars. In recent years, documented infection of dogs with L. canicola and L. icterohaemorrhagiae has been quite rare, but infection with serovars L. gryppotyphosa, L. pomona, and L. bratislava has increased in frequency.3 The prominence of these latter serovars stems from the use of vaccination and the greater exposure of unnatural hosts such as dogs to wildlife reservoir hosts in rural or suburban environments.1 For this reason, pharmaceutical manufacturers have developed newer vaccines designed to protect against infection with L. gryppotyphosa and L. pomona.3

Currently, the United States Department of Agriculture has not licensed any vaccine containing the serovar L. bratislava. As with most bacterins, immunity is not as long lasting as is immunity to viral antigens. Yearly boosters are recommended for at risk dogs, and immunity may not even last a complete year. Although leptospiral vaccines have historically been incriminated in more adverse vaccine reactions than other commonly used vaccines, the newer and "cleaner" subunit vaccines have lead to a reduction in the number of these adverse reactions.3

Public Health Considerations

In developed countries, leptospirosis continues to be a disease of considerable economic significance in animal husbandry, but the major burden of the human disease remains in tropical and subtropical developing countries.8 The majority of infections in people are among those who engage in water sports or who experience occupational exposure to wildlife or domestic animal hosts.1

Urine is the most important source of leptospiral contamination after acute infection. Veterinary clinicians and staff should wear protective latex gloves when handling any dog with possible leptospirosis, as well as blood and bodily fluids from the animal. Areas soiled by the dog’s urine should be cleaned with an iodine-based disinfectant (protective gloves should be worn during cleaning). Leptospires may continue to be shed in the urine for months despite clinical recovery and an effective immune response.6

References

1. Greene CE (ed): Infectious Disease of the Dog and Cat, 2nd ed. W. B. Saunders Co., Philadelphia, 1998, pp. 273–281.

2. Ward MP: Seasonality of canine leptospirosis in the United States and Canada and its association with rainfall. J Prev Vet Med 56:203-213, 2002.

3. Cohn LA: Leptospirosis. Proc Ann Meeting of Am Vet Med Assoc, 2003.

4. Langston CE: Leptospirosis. Proc Ann Meeting of Am Vet Med Assoc, 2002.

5. Nelson RW, Couto CG (eds): Small Animal Internal Medicine, 3rd ed. Mosby Publishing, St. Louis, 2003.

6. Wohl JS: Canine leptospirosis. Compend Contin Educ Pract Vet 18:1215-1225 & 1241, 1996.

7. Avdeeva MG: Hematological parameters in characterization of anemia in leptospirosis. Klin Lab Diagn 5:8-12, 2001.

8.Levett, PN: Leptospirosis. J Clin Microbiol Rev 14:296-326, 2001.

9. Jones CJ, Hunt RD, King NV (eds): Veterinary Pathology, 6th ed. Williams and Wilkins, Baltimore, 1997, pp. 467-471.

10. Leptospirosis Reference Laboratory, KIT Biomedical Research, Netherlands

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