Dermatological signs of canine leishmaniasis

Introduction

Leishmaniasis is a frequent and important infectious disease of dogs living in or coming from endemic areas. The causative agent is a single-celled parasite of the Leishmania genus, L. infantum, which is transmitted by phlebotomine sand flies in the Mediterranean area, although vertical transmissions of the parasite from pregnant bitches to their offspring and directly through blood transfusions have also been documented 1 3. Within endemic areas transmission of Leishmania occurs focally, so broad variations in the prevalence of infection may be seen in contiguous territories, depending mainly on the relative vector densities 1 2 3. This paper provides essential general information for a clinician faced with a case of canine leishmaniasis, with specific focus on managing the different dermatological pictures seen with the disease.

Infection and disease

Canine leishmaniasis is a classic example of an illness where the clinical signs can vary widely, from asymptomatic to severe clinical disease; this variation is intrinsically related to the interaction between the parasite, the arthropod vector and the canine immune system 1 3.

In canine leishmaniasis the immune response from T-helper CD4+ lymphocytes plays a pivotal role in tipping the balance from infection to disease. If the response is dominated by an exaggerated humoral (Th2) reaction, together with no or minimal cell-mediated (Th1) response, dogs generally develop a chronic, progressive disease, although it usually takes several weeks or months before signs become apparent following infection. By contrast, if the immune response is characterized by little or no Th2 reaction and a robust Th1-specific response against Leishmania, affected dogs are usually clinically healthy or have a mild, self-limiting form of the disease.

The spectrum of clinical presentation can vary widely, from infection with no obvious clinical findings but detectable laboratory abnormalities, to overt infection characterized by moderate or severe clinical signs (and laboratory abnormalities) that may require hospitalization. Additionally, both clinical and laboratory findings can be identical to many other infectious, immune-mediated, endocrine or neoplastic diseases. The most common clinical signs of canine leishmaniasis are enlargement of the lymph nodes and skin lesions. However, a broad and heterogeneous spectrum of signs may be detected on physical examination, including pale mucous membranes, weight loss or cachexia, polyuria/polydipsia, epistaxis, onychogryphosis, ocular lesions, lameness, lethargy, and fever. Significant laboratory findings can include thrombocytopenia, mild to moderate non-regenerative anemia, hyperproteinemia with hyperglobulinemia and hypoalbuminemia, and proteinuria.

Atypical forms of the disease have also been described, with gastrointestinal, neurological, musculoskeletal, cardiopulmonary, lower urinary tract or genital tract signs 1 3.

Dermatological disease

Dermatological signs are the most common clinical presentation of canine leishmaniasis; around 81-89 % of affected dogs will present with skin lesions 4 and in some cases they are the only clinical manifestation of the disease. Such lesions may be divided into typical (common and/or characteristic of the disease) or atypical (less common and/or more similar to lesions caused by other diseases) 5.

Typical lesions

Exfoliative dermatitis is considered to be the most common dermatological presentation. Typical lesions are whitish, rather sticky scales initially localized on the face and ears. Facial scales often distribute symmetrically around eyes (“butterfly sign”) and on the dorsum of the nose. As the disease progresses, lesions affect the trunk and extremities. Exfoliative dermatitis is usually non-pruritic and the skin may be partially ulcerated under the scales (Figure 1) 5 6.

Ulcerative dermatitis on bony prominences is the second most common dermatological presentation, with the carpal and tarsal regions most usually affected. Lesions are typically indolent, persistent ulcers, usually with elevated borders (Figure 2). It is hypothesized that persistent pressure causes secondary inflammation leading to the formation of an ulcer in an infected dog 5.

Onychogryphosis is classically characterized by excessive growth and abnormal curvature of the nails (Figure 3) 7. The prevalence of this sign varies widely (24-90% of cases) and may rarely be the only clinical sign; however, most dogs with leishmaniasis also have other skin lesions.

Persistent papular dermatitis may be a very common finding in endemic regions, but the exact prevalence is unknown 5. It has been suggested to be indicative of a protective immune response 8 9. Lesions start as a raised papule, probably at the site of inoculation in a less haired area such as inner pinnae, eyelids, dorsum of the nose, lips and caudal abdomen. The papules enlarge and can coalesce to form small plaques. A crust develops centrally, covering an ulcer with a raised edge and variable surrounding induration (Figure 4).

Atypical lesions

Ulcerative dermatitis can have various presentations. One possibility is ulceration of the nasal planum (Figure 5) which, when diffuse or located on the dorsum of the nose, can be indistinguishable from discoid lupus erythematosus (which is the main differential diagnosis, both clinically and histologically 10). Erosive, ulcerative lesions at mucocutaneous junctions can also be seen; all junctions may be affected. Signs have also been described at sites of previous cutaneous injury 11 12. Finally, ulcerative dermatitis can also develop due to cutaneous vasculitis from deposition of immunocomplexes; in this case, ulcers are located at distal extremities, such as tips of the pinnae, tail, digits and pads 5.

Muco-cutaneous nodular dermatitis is a relatively uncommon clinical presentation (2-17% of cases) described more frequently in Boxers. Clinically, these are single or multiple nodules of variable size (1-10 cm), usually located on the head, thorax and extremities. They are covered by hair and sometimes ulcerate. Lesions have been reported at mucocutaneous and mucosal junctions such as the mouth or genitalia (Figure 6) 5.

Pustular dermatitis is a clinical form described uncommonly in affected dogs, but if present is frequently generalized. Pustules are related to erythematous papules and epidermal collarettes, and are distributed symmetrically over the entire body surface. Pruritus is variable, but is often present and intense 5. It has been suggested that leishmaniasis is a risk factor for the development of an immune-mediated neutrophilic pustular dermatitis in dogs which is unresponsive to antibiotics 13 14.

Multifocal alopecia is rarely seen in canine leishmaniasis and is a consequence of an ischemic dermatopathy. As with ulcerative dermatitis due to vasculitis, it has been suggested that the cutaneous vascular damage is due to secondary deposition of immune complexes 5.

Naso-digital hyperkeratosis is atypical and often associated with other clinical manifestations of leishmaniasis, both typical and atypical. Greyish, thick and dry scales characterize the lesions. These are strongly adhered to the underlying skin and are sometimes accompanied by deep fissures, which can be painful, especially on the pads 5.

Diagnosis and staging

Since diagnosis of canine leishmaniasis is complex, an integrated approach is required, and should consider signalment, history, clinical findings, and laboratory tests to detect the parasite (via cytology, histopathology or PCR) or to evaluate the immune response of the host via qualitative or quantitative serology 15 16.

In most cases, and especially with typical lesions, demonstration of intralesional parasites can be sufficient to confirm the causal role of Leishmania. Skin cytology (Figure 7) or determination of parasitic DNA by PCR are the most practical ways to identify the parasite 5 17. However, demonstration of intralesional parasites in atypical lesions may be insufficient to confirm the causal role of Leishmania, especially in an endemic region, since infected dogs may have another concomitant disease 18 and it may be necessary to determine a favorable response to anti-Leishmania treatment in order to confirm that the parasite is responsible for the clinical signs.

It is essential to determine if clinical signs are due to Leishmania infection, or if illness is due to another disease. Dogs in the first category require specific leishmaniasis treatment irrespective of the disease severity 1 15, and must be staged for the disease, as this will determine the duration of treatment, the use of ancillary therapies, and the prognosis 1 3 15 16. Differentiation can be aided by the clinical classification developed by the Canine Leishmaniasis Working Group (CLWG) or Leishvet group*. Dogs in the second category do not require specific leishmaniasis treatment.

* www.gruppoleishmania.org or www.leishvet.org.

Treatment

All known drugs against Leishmania for dogs can lead to temporary or permanent remission of clinical signs, but complete elimination of the parasite is rare. Because of this, the aims of treatment are to induce a general reduction in the parasite load, to treat organ damage caused by the parasite, to restore an efficient immune response, to maintain clinical improvement once achieved, and to treat any relapse 19 20.

Therapeutic options and choice of drug regimens for sick dogs should be considered in light of the different clinical forms and stages of the disease, as exemplified by the case studies within this paper. The most widely used protocol is a combination of meglumine antimoniate (50 mg/kg SC q12H or 100 mg/kg q24H for at least 4 weeks) and allopurinol (10 mg/kg PO q12-24H for at least 12 months); this is suitable for all dogs with clinical patent leishmaniasis. An alternative is miltefosine (2 mg/kg PO q24H for 28 days) administered in combination with allopurinol (at the above dose) 19 20 21.

If treatment with meglumine or miltefosine is not possible, allopurinol can be administered alone at the above dosage for at least 12 months 19 20 22. Recent research has centered around using immunotherapy methodologies alongside conventional treatment for canine leishmaniasis, but more work is required 20.

Prognosis

In the majority of dogs with mild or moderate clinical stages, correct application of a therapeutic protocol should result in a clinical cure. In addition, treatment should produce a considerable decrease in parasite load for a prolonged period of time, which is necessary for reducing transmission of the parasite to sand flies. For dogs with a severe form of the disease, the above protocols offer a good chance of improvement, but may not result in a clinical cure. In this situation, particular if severe chronic renal disease is present, any ancillary treatment and the prognosis will be determined by the clinical signs 3 23.

Prevention

Preventive measures against Leishmania infection are essential in all dogs living in or visiting areas where the parasite is endemic. To date, two strategies have been shown to be effective and are becoming more commonly used 20 24 25:

1. prevention of infection by avoiding sand fly bites by regular use of a topical pyrethroid insecticide repellent; this is thought to be an effective tool in protecting dogs and also reduces the risk of human infection.

2. prevention of disease development after infection by vaccination and/or oral treatment with domperidone; this appears to be a good option to protect dogs when challenged by Leishmania.

However there is no guarantee that disease can be avoided totally. The preventive efficacy of pyrethroids is between 84-98% in individual dogs and close to 100% at population-level, whilst the preventive efficacy of vaccination is ~ 70% in individual dogs, and 80% using domperidone. Prevention strategies may be combined, but as yet it is uncertain that this approach increases the degree of protection compared to a single strategy 20 24 25.

Three clinical cases illustrating frequent aspects of cutaneous leishmaniasis

The main objectives when treating dogs with leishmaniasis are to reduce the parasite load, treat any organ damage, and restore an effective immune response. Once stabilized, it is important to keep the dog healthy and treat any clinical relapse. The therapeutic options should be considered in light of the different clinical forms and stages of the disease; the case studies demonstrate typical treatment regimes for the main dermatological clinical presentations seen with canine leishmaniasis.

Case 1

Signalment

Boxer, spayed female, 1.5 years of age

Clinical signs

General physical examination: weight loss with moderate but generalized lynphadenopathy. Skin lesions included exfoliative dermatitis with underlying ulceration on the face and the extremities (Figure 8); papular dermatitis on the inner pinnae and lips (Figure 9); nodular dermatitis on the trunk (Figure 10) and ulcerative dermatitis on the ear margins (Figure 11).

Diagnosis

Cytology on the papules, nodules and ulcers was positive for amastigotes. Moderate non-regenerative anemia, hypoalbuminemia, hypergammaglobulinemia. UPC ratio = 0.51; high positive ELISA

Treatment

Meglumine antimoniate for 4 weeks and allopurinol for one year (at the recommended dose) with follow-up at 30, 180 and 365 days after diagnosis. At Day 30 the lesions were in partial remission (Figure 12) (Figure 13), no new signs were noted, and serology was medium positive. At one year follow-up the dog was clinically healthy and serology was still medium positive. 

Case 2

Signalment

Crossbred, male, 5 months of age

Clinical signs

Papular dermatitis (lesions < 1 cm and with a central ulcer and/or crust) on the inner pinnae, eyelids, bridge of the nose and lips (Figure 14) (Figure 15) (Figure 16). 

Diagnosis

Cytology revealed macrophagic inflammation with some neutrophils and extracellular cocci. Nodular to diffuse pyogranulomatous inflammation on skin biopsies with positive Leishmania-specific immunohistochemistry (Figure 17a) (Figure 17b). Mild hypergammaglobulinemia; UPC ratio = 0.2; low positive ELISA.

Treatment

The prognosis for this clinical picture is good, although the optimal treatment regime is debatable; some cases recover without any treatment. Monotherapy with meglumine antimoniate for 4 weeks was chosen, with follow-up as for case 1. It is important to emphasize that a dog should return for specific anti-Leishmania treatment if there is a poor response to therapy. At Day 30, lesions were in remission (Figure 18) (Figure 19) (Figure 20), no new signs were noted, and serology was negative. The findings were the same at one-year follow-up.

Case 3

Signalment

Boxer, neutered male, 4 years of age

Clinical signs

Generalized papulo-pustular dermatitis on the inner pinnae, head, trunk and extremities (Figure 21) (Figure 22) (Figure 23) (Figure 24) and naso-digital hyperkeratosis (Figure 25).

Diagnosis

Cytology revealed neutrophilic inflammation with few extracellular cocci and acantholitic cells. Bacteriological culture and sensitivity tests yielded coagulase negative Staphylococcus spp. sensitive to various antibiotics. Moderate non-regenerative anemia, neutrophilic leukocytosis, hypoalbuminemia, marked hypergammaglobulinemia. UPC ratio = 1.3. High positive ELISA.

Treatment

The recommended treatment was as for case 1, along with doxycycline (10 mg/kg PO q24h) based on the results of the antibacterial sensitivity test. A week later the dog presented with apathy, anorexia, painful joints, fever and reluctance to walk, and the skin lesions had not improved despite treatment. Blood and urine tests were repeated but were unchanged. Skin biopsies revealed a subcorneal neutrophilic dermatitis with acantholysis; specific immunohistochemistry was positive for Leishmania. The diagnosis was generalized and pruritic non-antibiotic responsive pustular dermatitis. Prednisone (1 mg/kg PO q12H) was prescribed for the presumed concomitant immune-mediated diseases (i.e., dermatitis, glomerulonephritis and polyarthritis) and clinical improvement was noted a week later, and although intact pustules were still visible, pruritus had improved. At day 30, skin lesions were in partial remission and pruritus was absent; the UPC ratio had dropped to 0.9 with mild hypergammaglobulinemia. Antibiotic was then stopped and meglumine antimoniate, allopurinol and prednisone were continued. At day 60, papulo-pustular dermatitis had improved by 80% and pruritus was absent. Meglumine was then withdrawn, allopurinol maintained and the dose of prednisone was progressively reduced (25% reduction every 21 days). By day 90 there was only a mild pustular dermatitis with epidermal collarettes on the ventral abdomen (attributable to superficial pyoderma based on cytology) (Figure 26) (Figure 27). There were no clinico-pathological abnormalities and the UPC ratio was 0.4. At 180 days post-diagnosis there was a total resolution of clinical signs.

Leishmaniasis can cause a wide variety of clinical signs in dogs, and active infection can be debilitating in many patients. Identifying the disease can be problematic, and the clinician should adopt a structured approach to potential cases to ensure accurate diagnosis and staging of the disease. Treatment is usually long-term and requires frequent follow-up; recurrence of clinical signs is not uncommon as it is rare for the parasite to be eliminated completely. Because the dermatological signs can vary widely, the veterinarian should invariably consider leishmaniasis a possible diagnosis if a dog from an endemic area is presented with skin lesions.