Canine leishmaniosis - Part I: pathogenesis and clinical signs

Dr. Irina Matricoti, Veterinary Surgeon, Dipl. ECVD, European Specialist in Veterinary Dermatology

Leishmaniosis is an endemic disease in the Mediterranean basin, southern Europe, Central and South America, eastern Asia and northern Africa. The disease is caused by infection with a biphasic (with and without flagellum) protozoan of the genus Leishmania. There are several species of Leishmania, and the one of greatest importance in Europe to date is Leishmania infantum (1,2).

Pathogenesis

The dog is one of the main reservoirs, and therefore knowing the epidemiology, mode of transmission and prevention in this species is of fundamental importance, not only for animal care but also for public health issues, as leishmaniosis can also be contracted by humans.

In Europe, North Africa and Asia, the parasite is transmitted by a sandfly vector of the genus Phlebotomus, while in America by the genus Lutzomyia. The phlebotomus, in Italy mainly P. perniciosus, is active during the warm and humid months, between spring and early autumn with temperatures between 15°C and 28°C, and particularly between sunset and sunrise. It prefers poorly ventilated areas with high humidity, and can only move a few hundred metres. It is an insect with positive phototropism, so it tends to fly towards light sources in exactly the same way as common mosquitoes (e.g. towards the interior of houses) (1,3).

The sandfly becomes infected following a blood meal on a carrier animal, ingesting the protozoan in the form of an amastigote (without flagellum). In the intestine of the carrier, the protozoa multiplies and takes the form of a promastigote (with flagellum), then migrates into the buccal apparatus of the phlebotomus, which then becomes infectious for new animals within 4-25 days after ingestion.

Following a blood meal, the sandfly inoculates the parasite into the host, which is phagocytosed by macrophages. Here the parasite loses its flagellum, thus becoming an amastigote, and replicates asexually until cells rupture and release new elements infecting other contiguous cells. In susceptible individuals, the parasite disseminates throughout the body, infecting different cell types and replicating in phagocytic cells. The parasite persists mainly in the bone marrow, and from there it can disseminate again, causing relapses of the disease during the patient's lifetime. In more resistant individuals, whose immune system is able to stem the infection, the parasite tends to remain confined to the skin and regional lymph nodes.

Other reported forms of infection are the sexual route, the transplacental route and blood donations. Transmission via other vectors such as ticks and fleas is also hypothesised, although not yet proven (1-3).

Once infected, the patient develops an immunological reaction, the type of which will determine the course of the disease. In particularly susceptible individuals, a Th2 antibody-mediated response prevails. In addition to being ineffective in eliminating an intracellular parasite, antibodies are also harmful because if produced in excess they cause the formation of immune complexes, which damage the renal glomeruli, the vessel walls, and in general all the filtering membranes where they can be deposited. Conversely, in resistant individuals a Th1 cell-mediated response prevails, inducing parasite elimination by macrophages (1-3).

There are numerous factors that determine a subject's resistance or susceptibility, including genetic predisposition, the presence of co-morbidities and the route of transmission. For example, there are breeds that are more susceptible than others, such as the Cocker spaniel, Rottweiler, Boxer and German Shepherd, while it is known that in the Ibizan Hound the disease is quite rare. Age may also play a role, as the disease is most frequently reported in individuals under three years of age or over eight years of age. Finally, intravenous infection (e.g. following transfusions) results in generally more severe symptoms (1-3).

Clinical signs

Due to the different immune system responses of infected dogs, clinical signs and haematological changes may be variable and not always present. For the purposes of therapy, it is therefore necessary to differentiate between infected but not ill subjects (carriers) and infected and ill subjects. Sometimes, especially in the case of concomitant diseases with similar clinical alterations (e.g. tick-borne diseases), it is not easy to differentiate between the two groups. Moreover, a carrier subject could at any time become symptomatically ill.

The most relevant systemic clinical signs are lymphadenomegaly, splenomegaly, hyperthermia, inappetence and lethargy. If renal involvement is present, polyuria and polydipsia are also observed. The most frequent haematobiological changes are non-regenerative normochromic normocytic anaemia, hypoalbuminemia and hypergammaglobulinemia (polyclonal), and azotemia and creatinine elevation in patients with renal involvement. In these patients, urinalysis may show proteinuria with an increased urinary protein/creatinine ratio (2,4).

Dermatological lesions are present in more than 80% of sick patients, and are particularly varied, so that leishmaniosis is among the differential diagnoses of many skin diseases (4). Exfoliative dermatitis is the most common skin form and is characterised by the appearance of large white asbestiform (psoriasiform) scales, often initially localised on the ears and head and then extending to the entire body.

Ulcerative dermatitis, probably the result of vasculitis due to the deposition of immune complexes, is characterised by the appearance of erosive lesions that evolve into localised ulcers on bony prominences and extremities, e.g. fingertips or apex of the ears, and on mucocutaneous junctions (2,4).

Papular dermatitis, probably a cellulomediated reaction at the site of inoculation of the parasite, is characterised by the appearance of non-itchy umbilicated papules on areas poorly covered with hair such as the ear pinnae, eyelid rims, the dorsal nose or the abdomen. As this form usually presents low or negative antibody titres, it is believed to be associated with a favourable prognosi,s as it is indicative of a strong cell-mediated immune response by patients, mostly young, who are able to clear the infection. Most of these subjects have a negative lymph node PCR, indicative of a form of the disease that is not disseminated but rather confined to the skin (4-6).

Nodular dermatitis is characterised by the appearance of multiple nodules on skin or mucous membranes. This form is most frequently described in dogs of the Boxer breed. In contrast to the papular form, a large number of parasites are present within them, which can be easily visualised by cytological or immunohistochemical examination, so this form is believed to be associated with an impaired cell-mediated response and a state of increased susceptibility to infection (4).

Sterile pustular dermatitis is among the most controversial forms, characterised by the appearance of pustules often (but not always) containing acantholytic cells, and frequently associated with itching. Although this form has been mentioned in the literature in several scientific reviews, a case series collecting 22 subjects suffering from pustular dermatitis and leishmaniosis has only recently been published (7). The author of this publication deliberately avoids referring to this form as ‘pustular leishmaniosis’, rather using terms such as pustular dermatitis in patients with leishmaniosis, as the pathogenesis of the lesions is unclear to date. There is certainly a statistically significant association between this dermatosis and leishmaniosis, since in endemic areas the risk of presenting pustular dermatitis in leishmaniosis patients is 76 times greater than in unaffected patients (8). It is conceivable that the dysregulation of the immune system caused by the parasitic infection favours the onset of a pemphigus-like autoimmunity, or that in (non-sick) leishmania carriers the onset of a pustular autoimmune disease aggravates the disease state of these patients (8). In the case series, subjects suffering from pustular dermatitis in the course of leishmaniosis almost all presented a medium-high antibody titre, an abnormal electrophoresis and a reduced albumin/glubulin ratio. In these patients, the exclusive administration of antileishmanial therapy was ineffective, so that immunodulatory or immuosuppressive therapies, such as glucocorticoids, azathioprine (not to be combined with allopurinol), tetracycline or doxycyline in association or not with nicotinamide, were required to achieve remission of the pustular dermatitis (7,8). The prognosis in these patients is particularly reserved, given the need for immunosuppressive therapies in animals with leishmaniosis, but once remission of pustular dermatitis has been achieved, immunomodulatory therapies can be gradually reduced and discontinued without the need to continue them for life (8).

Other clinical manifestations of leishmaniosis are onychogryphosis and naso-digital hyperkeratosis and depigmentation of the nose and mouth, possibly resulting from interface dermatitis with basement membrane damage and pigment incontinence (2).

Finally, the occurrence of glossitis or multiple oral nodules on the tongue or gums is reported. It is hypothesised that this localisation is a consequence of accidental ingestion of phlebotomes that inoculate the parasite at this site or the migration of already infected macrophages to sites of oral infection (9,10).

Leishmaniosis, being a systemic disease, also presents non-dermatological manifestations, such as ophthalmic problems, in particular uveitis or dry keratoconjunctivitis due to the destruction of the Meibonium glands, epistaxis, myositis especially of the masticatory muscles, arthritis due to immune complexes, hepatitis, colitis, meningoencephalitis, or problems of the genital apparatus. These manifestations are a consequence of granulomatous inflammation in the tissues of the various organs, hypergammaglobulinaemia causing hyperviscosity and the deposition of immune complexes in the filter membranes (1,2) .

Bibliographic references

1. Morales-Yuste, M., Martín-Sánchez, J., & Corpas-Lopez, V. (2022). Canine leishmaniasis: Update on epidemiology, diagnosis, treatment, and prevention. Veterinary Sciences, 9(8), 387.

2. Koutinas, A. F., & Koutinas, C. K. (2014). Pathologic mechanisms underlying the clinical findings in canine leishmaniosis due to Leishmania infantum/chagasi. Veterinary Pathology, 51(2), 527-538.

3. Solano-Gallego, L., Koutinas, A., Miró, G., Cardoso, L., Pennisi, M. G., Ferrer, L., ... & Baneth, G. (2009). Directions for the diagnosis, clinical staging, treatment and prevention of canine leishmaniosis. Veterinary parasitology, 165(1-2), 1-18.

4. Saridomichelakis, M. N., & Koutinas, A. F. (2014). Cutaneous involvement in canine leishmaniosis due to L eishmania infantum (s yn. L. chagasi). Veterinary Dermatology, 25(2), 61-e22.

5. Ordeix, L., SOLANO‐GALLEGO, L. A. I. A., Fondevila, D., Ferrer, L., & Fondati, A. (2005). Papular dermatitis due to Leishmania spp. infection in dogs with parasite‐specific cellular immune responses. Veterinary dermatology, 16(3), 187-191.

6. Lombardo, G., Pennisi, M. G., Lupo, T., Chicharro, C., & Solano-Gallego, L. (2014). Papular dermatitis due to Leishmania infantum infection in seventeen dogs: diagnostic features, extent of the infection and treatment outcome. Parasites & vectors, 7, 1-11.

7. Colombo, S., Abramo, F., Borio, S., Albanese, F., Noli, C., Dedola, C., & Leone, F. (2016). Pustular dermatitis in dogs affected by leishmaniosis: 22 cases. Veterinary dermatology, 27(1), 9-e4.

8. Bardagí, M., Monaco, M., & Fondevila, D. (2020). Sterile or nonantibiotic‐responsive pustular dermatitis and canine leishmaniosis: a 14 case series description and a statistical association study on 2420 cases. Veterinary dermatology, 31(3), 197-e41.

9. Villanueva‐Saz, S., Pérez, E., Yzuel, A., Gomez, A., & Verde Arribas, M. T. (2024). Proliferative papulo‐nodular glossitis due to Leishmania infantum in a dog. Veterinary Record Case Reports, 12(1), e779.

10.Blume, G. R., Eloi, R. S. A., Silva, F. P., Eckstein, C., Santos, R. L., & Sant’Ana, F. J. F. (2019). Oral lesions in dogs with visceral leishmaniosis. Journal of comparative pathology, 171, 6-11.