Leishmaniasis

Synopsis

CAPC Recommends

• Consider a diagnosis of leishmaniasis in any dogs with a travel history to an endemic area; dogs in North America are not known to be infected by sand fly vectors although direct vertical and horizontal transmission does occur.
• Diagnose leishmaniasis based on clinical signs, antibody tests, or PCR; diagnosis can be confirmed by identifying organisms in aspirates, biopsy samples, or touch preparations of affected tissues.
• There are a variety of treatment options available (see Treatment guidelines), but recognize that relapses are common and no drug is consistently curative.

Species

• Leishmania infantum is the most common and important cause of canine leishmaniasis worldwide. Although referred to as canine leishmaniosis in most of the world, many in North America still use the historic form leishmaniasis; CAPC considers the two terms synonymous. Other Leishmania spp. reported from dogs in the Americas include L. amazonensis, L. guyanensis, L. naiffi, L. panamensis, L. peruviana, L. mexicana, L. donovani, and L. braziliensis. Leishmania spp. are also occasionally reported from cats. In areas where these parasites are endemic, cats are at risk of infection.

Overview of Life Cycle

• The life cycle of Leishmania spp.  involves two hosts—a vertebrate (including rodents, canids, or humans) and an insect (sand fly). In regions where these infections are endemic, phlebotomine sand flies (primarily the genus Lutzomyia in the New World; albeit other genera are suspected) are the vectors for transmission.
• Although phlebotomine sand flies are present in eastern North America, vector-borne transmission of Leishmania spp. has not been confirmed in this region. Instead, transmission is thought to be maintained by direct vertical and horizontal transmission.

Stages

• In mammalian hosts, Leishmania spp. occur as amastigotes (2 to 3 μm in diameter) solely within mononuclear phagocytes in the skin, bone marrow, and visceral organs.
• Leishmania spp. occur as flagellated, extracellular promastigotes in the gut of sand fly vectors. Infection occurs when a feeding sand fly deposits metacyclic promastigotes into the dermis.

Disease

• Infection does not invariably lead to illness. In fact, most infected dogs remain asymptomatic and may never develop clinical manifestations. In endemic regions, the prevalence of disease is often less than 10% and only about 1 in 5 infected dogs are considered likely to develop clinical disease.
• The variable course of disease that occurs following infection is thought to be due to differences in the immune response of individual dogs. Certain breeds (e.g. German shepherd, Boxers, Cocker spaniels) are considered more likely to develop disease. In the United States, leishmaniasis is considered endemic in many foxhound kennels and is most commonly identified in this breed.
• Disease is most commonly seen in dogs less than 3 years of age and older than 8, and may be associated with other immunocompromising conditions; some studies have shown disease is more common in male dogs although this is not a consistent finding.
• Skin lesions are the most common sign associated with clinical leishmaniasis in endemic areas and may include regional (often facial) alopecia and non-pruritic, ulcerative, nodular, or papular dermatitis which may or may not be complicated by bacterial pyoderma.
• Other clinical manifestations include chronic wasting, epistaxis, diarrhea, keratoconjunctivitis, conjunctivitis, blepharitis, ocular signs (anterior uveitis, retinitis), severe muscle atrophy, swollen limbs and joints, lameness, lymphadenopathy, polyarthritis, neurological signs, and protein-losing nephropathy, which may lead to renal failure. Assessment of renal function in all infected dogs is critically important.
• Normocytic normochromic non-regenerative anemia, thrombocytopenia, leukopenia or leukocytosis, hypoalbuminemia, hyperglobulinemia, hyperamylasemia, and azotemia are the most frequently detected laboratory abnormalities.

Prevalence and Geographic Distribution in Dogs

• Leishmania infantum is endemic in much of the Mediterranean basin (e.g., Italy, Spain and Portugal), the Balkans, central and southwest Asia, north and northwest China, north and sub-Saharan Africa, and parts of Central and South America.
• Visceral leishmaniasis, which may present with primarily cutaneous or visceral signs, is occasionally diagnosed in the United States in dogs of any breed imported from southern Europe or South America where the infection is endemic.
• Since the 1980s, autochthonous leishmaniasis has been reported in kenneled foxhounds in the United States, and infection is now recognized in foxhounds from many eastern U.S. states and Canadian provinces. In the at-risk population of foxhounds, more than 20% of dogs test positive by quantitative PCR.
• In recent years there have been a rise in the reports of autochthonous leishmaniasis cases in non-foxhound breeds. Many of these cases can be attributed to vertical transmission or travel to endemic areas. However, there are cases where there is no history of travel or known source of vertical transmission, thus raising the suspicion of possible vector-borne transmission.
• A recent retrospective, descriptive study found that 6.4% of dogs suspected of leishmaniasis were infected with L. infantum in the United States and Canada. While majority of the dogs were imported or had a history of travel to endemic areas, 13% of dogs with available travel history had not traveled outside of the United States or Canada.
• Isolates obtained from foxhounds in North America indicate that the agent is L. infantum MON-1, which is also the predominant zymodeme found in infected dogs and humans in southern Europe.

Host Associations and Transmission Between Hosts

• Phlebotomine sand flies of the genus Lutzomyia are the primary vectors of transmission in the Americas.
• Only female sand flies feed, preferring the less haired areas of skin including the head, bridge of nose, ear pinnae, and inguinal areas. Feeding sand flies acquire amastigotes from infected dermis and later transmit metacyclic promastigotes.
• Once in the host, the promastigote is phagocytosed by macrophages and transforms into an amastigote, surviving and multiplying within parasitophorous vacuoles.
• Dogs are considered the primary reservoir host for sand fly transmitted L. infantum in endemic countries although infections are also reported in cats.
• Leishmania infantum can also be transmitted directly from dog to dog by contamination with blood and secretions, venereally, as well as transplacentally from an infected dam to her pups. Current evidence suggests that transmission among dogs in North America is limited to these direct dog-to-dog mechanisms although sand fly transmission cannot be entirely eliminated as a possible, additional route of infection.
  

Prepatent Period and Environmental Factors

• The course of canine infection with Leishmania infantum is highly variable.
• Canine leishmaniasis may become patent within 1-2 months of initial infection in some dogs. Alternatively, infections in other dogs remain sub-patent for more than a year, and a few dogs become PCR-negative for several months before infections recrudesce and progress. 
• Sand flies are active at dusk and dawn during the warmer months of the year particularly in areas with high relative humidity.
• In temperate areas, infection is largely maintained in dog reservoirs through the winter months when sand fly activity ceases.

Diagnosis

• Diagnosis of canine leishmaniasis is based on the presence of clinical signs together with positive specific antibody assay.  Infection can be confirmed by demonstration of the parasites (amastigotes) on touch prep stained (Wright-Giemsa) slides or in cultures of tissue aspirates or biopsy specimens of the spleen, liver, bone marrow, or lymph nodes.
• Diagnostic antibody tests include the indirect fluorescent antibody assay (IFA), direct agglutination assay, and enzyme immunoassay (EIA). These tests vary in sensitivity and specificity, and although they verify presence of antibody, they do not prove or rule out active infection. Recently, several rapid point-of-care tests have been developed to detect antibodies against Leishmania spp., however, many are not currently available in the United States.
• These assays may give false-positive reactions with sera of dogs imported from endemic areas that have been vaccinated against Leishmania spp. and in dogs infected by Trypanosoma cruzi, another protozoan that sometimes infects dogs in the Americas.  However, assays that utilize certain antigens, such as rK39, have high specificity for Leishmania spp. therefore lowering the likelihood of cross-reactivity to other protozoal species.
• Polymerase chain reaction (PCR) assays are available at some veterinary diagnostic laboratories and can be helpful for confirming infection in individual patients and as part of an overall control program. Tissue samples (e.g. skin, lymph node, spleen, bone marrow) provide the highest sensitivity. Blood and urine can also be utilized for PCR; however, the sensitivity is much lower.
• Renal function should be carefully evaluated on all infected dogs; persistent renal proteinuria and non-regenerative anemia should raise the index of suspicion for canine leishmaniasis in any at risk dog.
  

Treatment

• Canine leishmaniasis is less amenable to treatment than this infection is in humans. Anti-leishmanial drugs used in dogs include pentavalent antimonials and allopurinol; to date, no drug has proven to be consistently curative for visceral leishmaniasis in dogs.
• Care should be taken when using human drugs to treat dogs in endemic areas due to the risk of selection for resistance.
• Antimonial compounds can suppress and sometimes cure the infection; such compounds include meglumine antimoniate (Glucantime) in Europe and sodium stibogluconate (Pentostam) in the United States. Although clinical improvement may occur in response to chemotherapy, relapses are common, and chemotherapeutic elimination of L. infantum has not been consistently achieved with any drug tested to date.
• Maintenance therapy with allopurinol (10 mg/kg by mouth twice daily) decreases parasitemia, maintains infected dogs in an asymptomatic state, and decreases the likelihood of direct or vector transmission. However, treatment with allopurinol for prolonged periods increases the risk for xanthine urolithiasis and renal mineralization. A low-purine diet can help mitigate the risk for xanthine urolithiasis.
• Combination therapies are often used when treating canine leishmaniasis. One of the more common protocols is allopurinol (10 mg/kg by mouth twice daily for 6 to 12 months or longer) and meglumine antimoniate (100 mg/kg subcutaneously once daily or divided into two doses for 4 to 6 weeks). Other therapies include the use of allopurinol (10 mg/kg by mouth twice daily for 6 to 12 months or longer) and miltefosine (2 mg/kg by mouth once daily for 4 weeks); however, one study found evidence of resistance in vitro to miltefosine and amphotericin B when using this combination therapy against L. infantum.
• The use of immunomodulatory therapies, such as domperidone (0.5 mg/kg by mouth once daily for 4 weeks), and dietary nucleotides with AHCC (active hexose correlated compound) have also shown some benefit in the treatment of canine leishmaniasis.
• Amphotericin B has also been used to treat infections; however it is more toxic and considered less effective than allopurinol.
• Kidney disease, if present, should be staged and managed according to IRIS guidelines.
  

Control and Prevention

• In endemic areas where vector transmission is the primary mode of transmission, vector control limits transmission; use of persistent repellent insecticides such as permethrin or deltamethrin helps protect dogs from contact with vectors, reducing the risk of transmission.
• In regions where the infection is not endemic, euthanasia of infected dogs is sometimes recommended to prevent leishmaniasis from becoming endemic.
• Some foxhound kennels in North America have adopted a test and elimination approach in an effort to reduce the overall burden of disease on the breed.

Public Health Considerations

• In areas where L. infantum is endemic and transmitted by insect vectors, it is an important agent of human disease and dogs are considered the most important peridomestic reservoir host. However, ownership of an infected dog has not been shown to increase the risk of infection in the family.
• The practice of eliminating seropositive dogs (euthanasia program) is occasionally practiced but there is no evidence to support that this works to reduce the rate of human or canine infection in a given area. Efforts to stop this practice are ongoing.
• If sand flies in North America are able to transmit L. infantum from infected to susceptible dogs, then vector transmission from infected dogs to humans is also possible.
• To date, no autochthonous human cases of visceral leishmaniasis have been reported from the United States, and there are no data to suggest vector transmission is occurring among dogs in North America.
• A related parasite, Leishmania mexicana, is considered endemic in the United States and is responsible for cutaneous leishmaniasis which causes skin sores such as papules, nodules, and ulcers.
  

Selected References

• Baneth G, Koutinas AF, Solano-Gallego L, Bourdeau P, Ferrer L. 2008. Canine leishmaniasis – new concepts and insights on an expanding zoonosis: part one. Trends Parasitol 24(7): 324-330.
• Boggiatto PM, Gibson-Corley KN, Metz K, Gallup JM, Hostetter JM, Mullin K, Petersen CA. 2011. Transplacental transmission of Leishmania infantum as a means for continued disease incidence in North America. PLOS Neglect Trop Dis 5(4):e1019.

• Cavalera MA, Gernone F, Uva A, D’Ippolito P, Roura X, Paltrinieri S, Zatelli A. 2021. Effect of domperidone (leisguard®) on antibody titers, inflammatory markers and creatinine in dogs with leishmaniosis and chronic kidney disease. Parasit Vectors 14:525.
• Dantas-Torres F. 2024. Canine leishmaniasis in the Americas: etiology, distribution, and clinical and zoonotic importance. Parasit Vectors 17:198.
• Gin TE, Lashnits E, Wilson JM, Breitschwerdt EB, Qurollo B. 2021. Demographics and travel history of imported and autochthonous cases of leishmaniosis in dogs in the United States and Canada, 2006 to 2019. J Vet Intern Med 35:954-964.
• Gonçalves G, Campos MP, Gonçalves AS, Medeiros LCS, Figueiredo FB. 2021. Increased Leishmania infantum resistance to miltefosine and amphotericin B after treatment of a dog with miltefosine and allopurinol. Parasit Vectors 14:599.
• Grammicia M. 2011. Recent advances in leishmaniasis in pet animals: epidemiology, diagnostics, and anti-vectorial prophylaxis. Vet Parasitol 181: 23-30.
• Miró G, Segarra S, Cerón JJ< Ferrer L, Solano-Gallego L, Montell L, Costa E, Teichenne J, Mariné-Casadó R, GALILEI trial Group, Roura X. 2024. New immunomodulatory treatment protocol for canine leishmaniosis reduces parasitemia and proteinuria. PLoS Negl Trop Dis 18(12).
• Solano-Gallego L, Koutinas A, Miro G, Cardoso L, Pennisi MG, Ferrer L, Bourdeau P, Oliva G, Baneth G. 2009. Directions for the diagnosis, clinical staging, treatment, and prevention of canine leishmaniasis. Vet Parasit 165:1-18.