Etiology and Epidemiology

The leishmaniases are a group of zoonotic vector-borne diseases caused by various species of the protozoa Leishmania, which are primarily transmitted by sandflies. Around 30 species of Leishmania exist worldwide, and at least 20 species cause disease in humans, although the taxonomy of Leishmania spp. has been highly debated.2,3 There are two subgenera of Leishmania, Leishmania and Vianna, which develop in the foregut or the hindgut/midgut of the sandfly vector, respectively. Human and animal disease due to Leishmania spp. is distributed across five continents (Africa, Asia, Europe, and the Americas) and nearly 100 countries (Figure 74-1). Disease syndromes in humans are divided into cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML), and visceral leishmaniasis (VL). Disease syndromes in dogs are divided into visceral leishmaniosis and American tegumentary leishmaniosis, a localized cutaneous form that occurs in parts of South America. The term ‘leishmaniosis’ as opposed to ‘leishmaniasis’ is preferred to distinguish the disease in animals from that in humans.

Leishmania species are transmitted by female sandflies of the genus Phlebotomus in the Old World (Africa, Asia, and Europe) and Lutzomyia in the New World (i.e., the Americas). The regional prevalence of leishmaniasis, and the type of disease syndrome that develops, varies with the infecting Leishmania species present, sandfly species in the region, and host responses to infection. Some sandfly species transmit certain Leishmania species primarily to humans (anthroponotic leishmaniasis), whereas other sandfly species transmit Leishmania species to mammalian host species, such as dogs, cats, and rodents. Dogs and rodents are important reservoirs for Leishmania infection of humans (zoonotic leishmaniasis). Thus, the major mammalian reservoirs for the disease in a region depend on the Leishmania species and the sandfly species present.

The life cycle of Leishmania alternates between two major forms: the promastigote and the amastigote (Figure 74-2). The promastigote resides in the gut of the sandfly vector and is an elongated, flagellated form. Promastigotes are inoculated into tissues when the sandfly feeds, where they are phagocytized by macrophages in the dermis and transform into intracellular, nonmotile, ovoid, or round amastigotes. The amastigotes survive and replicate within macrophage phagolysosomes, and eventually the infected macrophages rupture. Released amastigotes then infect other macrophages that have been attracted to the site of infection. If the infected host fails to control the infection, amastigotes disseminate via regional lymphatics and the blood to infect the entire reticuloendothelial system. Intracellular amastigotes that are ingested by a female sandfly during feeding convert back into promastigotes over a period of about 1 week, and replication of promastigotes within the sandfly completes the life cycle. Sandflies breed in cracks in the walls of dwellings, rubble, and in rodent burrows, feed primarily at night, and fly a maximum of 2.5 km from their breeding sites. As a result, the prevalence of infection in dogs can vary considerably between adjacent regions. Lesser modes of transmission of Leishmania spp. include vertical transmission from bitches to puppies, venereal transmission, and blood transfusion.4–7 These modes of transmission become more obvious in regions where suitable sandfly vectors do not exist. Aggressive interactions between dogs also have the potential to transmit infection, but this route has not been proven.

Canine visceral leishmaniosis in dogs and cats is caused by Leishmania infantum (also referred to as Leishmania chagasi in Central and South America). L. infantum is endemic in the Mediterranean basin, the Middle East, and Asia and may have been introduced to Latin America by early explorers and their domestic dogs.⁸ Because leishmaniosis has a long incubation period and prolonged disease course, travel-related leishmaniosis in dogs and cats is diagnosed sporadically in regions where sandfly transmission does not occur, such as parts of Scandinavia, Switzerland, Japan, the United Kingdom, and the western United States (most often in dogs imported from southern Europe).^9–13 In highly endemic regions of the Mediterranean and Brazil, infection rates among dogs vary widely but may reach 80%.^14–17 At least 2.5 million dogs are infected in southwestern Europe alone.¹⁴ The disease may be spreading northward in Europe, and has recently appeared in nontraveled dogs in countries such as Germany and Hungary.^5,18,19 Spread of Leishmania spp. into new areas can occur when humans bring infected dogs into regions where competent insect vectors exist, or when sandfly populations expand as a result of factors such as climate change.

Risk factors for infection in dogs include age at least 2 years, prolonged exposure to the outdoors, lack of topical insecticide use, and, in some studies, a short haircoat.20–23 Some authors have described a bimodal age distribution that peaks at 3 years and at greater than 8 years of age.²⁴ Sex is not an important risk factor for infection. Factors that promote proliferation of sandfly populations, such as poor sanitation and limited garbage collection, as well as the occurrence of stray dogs around homes, also put dogs at risk of infection.²⁵ In Europe, German shepherd dogs, boxers, Rottweilers, cocker spaniels, and Dobermans may be at increased risk for leishmaniosis; the Ibizan hound in Spain appears to be resistant to clinical disease.^24,26–29 Concurrent diseases are common in dogs with leishmaniosis in endemic regions and include transmissible venereal tumor,³⁰ demodicosis,³¹ sarcoptic mange,³² and a variety of other vector-borne diseases such as canine monocytic ehrlichiosis, babesiosis, hepatozoonosis, and dirofilariasis.^32–36 Concurrent lymphoma has also been described.³²

Uncommonly, dogs worldwide are infected by other species of Leishmania, which include Leishmania donovani, Leishmania tropica, Leishmania braziliensis, Leishmania peruviana, Leishmania mexicana, Leishmania panamensis, Leishmania guyanensis, Leishmania amazonensis, and other as-yet-uncharacterized species.37–45 L. braziliensis, L. guyanensis, and L. panamensis have been isolated from dogs with American tegumentary leishmaniosis. Outbreaks of American tegumentary leishmaniosis have occurred in humans and dogs.⁴³

Signs and Their Pathogenesis

The outcome of Leishmania spp. infection is variable. Some dogs completely eliminate the infection, and a small percentage of dogs develop severe, life-threatening disease. Some dogs remain persistently but subclinically infected, with the possibility of reactivation later in life with immunosuppression; these dogs also act as reservoir hosts and can infect sandflies.⁵² In general, dogs that mount strong T-cell–mediated immune responses eliminate the infection, whereas those that mount weak cell-mediated immune responses and marked, nonprotective humoral (IgG) immune responses develop clinical disease.⁵³ Host genetic factors are important in determining progression to clinical disease, and several candidate genes have been identified in dogs that may influence susceptibility.^28,54–56 When clinical disease appears, it occurs after a long incubation period (up to 7 years) and varies from mild papular or exfoliative dermatitis to severe disseminated disease due to massive proliferation of histiocytes, B lymphocytes, and plasma cells in reticuloendothelial tissues and immune-mediated consequences of chronic, persistent infection.

Cutaneous lesions most commonly manifest as alopecia, scaling, and/or ulceration but can be nodular or papular (Figure 74-3). They are often noticed before signs of systemic infection develop, despite the fact that they occur as a consequence of parasite dissemination. Many dogs also develop onychogryphosis (abnormally long or brittle claws).

Systemic signs of visceral leishmaniosis include fever, weight loss, muscle atrophy, inappetence, and lethargy; oral ulceration; progressive splenomegaly and lymphadenomegaly; mucosal pallor due to anemia; and rarely, hepatomegaly (Table 74-1). Development of autoantibodies and circulating immune complexes is thought to lead to immune-mediated thrombocytopenia and/or thrombocytopathia and signs such as epistaxis or melena, lameness and joint swelling due to immune-mediated polyarthritis, myositis, uveitis, vasculitis, and glomerulonephritis.^57–62 Positive antinuclear antibody tests are found in up to 50% of dogs tested.^32,61,63 Many dogs also have positive Coombs’ tests.^32,63

Glomerular injury ultimately culminates in nephrotic syndrome and/or failure of tubular function for many dogs, with polyuria and polydipsia, vomiting, diarrhea, and dehydration. Renal failure may occur in the absence of other lesions.³² Anemia may be due to a combination of factors that include blood loss, inflammation, renal failure, immune-mediated destruction, and marrow aplasia or hypoplasia. In addition to uveitis, other ocular lesions include blepharitis, conjunctivitis, panophthalmitis, and keratoconjunctivitis. Keratoconjunctivitis results from direct infection of the lacrimal gland by Leishmania.⁶⁴

Atypical presentations of canine visceral leishmaniosis have also been reported. Almost any organ can be affected, with reports of Leishmania prostatitis and infertility⁶⁵; nodular lesions of the tongue and other mucosal surfaces66,67; pancreatitis⁶⁸; gastrointestinal tract, myocardial, or pulmonary involvement^69–71; osteomyelitis^72,73; meningitis⁷⁴; and granuloma formation within the spinal cord.⁷⁵

American Tegumentary Leishmaniosis

American tegumentary leishmaniosis in dogs is characterized by development of a nodular skin lesion at the site of a sandfly bite that enlarges and eventually may ulcerate. Lesions most often occur on regions of the body that have less hair, such as the nose, perineal region, scrotum, and pinnae.43,76

Physical Examination Findings

Physical examination findings in dogs with visceral disease include lethargy, muscle atrophy or cachexia, variable and typically low-grade fever, focal or generalized peripheral lymphadenomegaly, and hepatosplenomegaly on abdominal palpation (Figure 74-4). Lymphadenomegaly can be severe and be suggestive of lymphoma. Although not always detected, skin lesions consist of scaling and crusting, hyperkeratosis, alopecia, erythema, and cutaneous ulceration and may be nonpruritic or pruritic. They most often occur on the limbs, pinnae, muzzle, and periocular regions. Mucocutaneous lesions can also occur. Ocular involvement may be associated with mucopurulent ocular discharge, blepharitis, and anterior uveitis. Onychogryphosis may be present. Lameness or reluctance to move may be associated with joint swelling, crepitus, and pain.⁷² Epistaxis may also be noted.

Laboratory Abnormalities

Diagnostic Imaging

Abdominal radiography or ultrasonography in dogs or cats with visceral leishmaniosis can reveal abdominal lymphadenomegaly, splenomegaly, and hepatomegaly. Radiographic lesions of long bones in dogs with bone involvement consist of soft periosteal proliferation, increased or decreased intramedullary opacity, and/or cortical and medullary destruction.63,72 Lesions tend to be bilateral and symmetrical. Joint radiographs in dogs with signs of arthritis may reveal erosive changes, or arthritis may be non-erosive.

Microbiologic Tests

Culture

Leishmania spp. can be isolated in culture from specimens such as lymph nodes, skin biopsies, spleen, or bone marrow, although special media and expertise are required, and incubation times of up to 30 days may be needed.

Pathologic Findings