Leishmaniasis is a chronic disease caused by flagellate protozoa of the genus Leishmania, of which there are over 20 species. Leishmania parasites are obligate intracellular parasites transmitted by the bite of infected female sandflies of the Phlebotomus and Lutzomyia genera. Leishmaniasis is essentially a zoonotic disease. The main reservoirs are dogs and rodents, but there are 2 cases for which humans are the main reservoirs: Leishmania donovani and Leishmania tropica.

The estimated incidence of leishmaniasis according to the World Health Organization is 700 000 to 1 million cases a year, of which 50 000 to 90 000 correspond to visceral leishmaniasis (VL).1 Approximately 95% of all cutaneous leishmaniasis (CL) cases occur in South America, the Mediterranean Basin, the Middle East, or Central Asia. LV, by contrast, is predominant in Brazil, East Africa, and India. In 2018, over 85% of new CL cases reported to the WHO were from Afghanistan, Algeria, Bolivia, Brazil, Colombia, Iran, Iraq, Pakistan, Syria, and Tunisia, while over 95% of new LV cases were from Brazil, China, Ethiopia, India, Iraq, Kenya, Nepal, Somalia, and Sudan.1 Finally, over 90% of new mucocutaneous leishmaniasis (MCL) cases were reported in 4 countries: Brazil, Bolivia, Ethiopia, and Peru.1

Leishmaniasis has traditionally been classified as Old World or New World depending on its geographic location. Old World leishmaniasis occurs in Asia, Africa, and Europe, and is mostly caused by L tropica, Leishmania major, Leishmania aethiopica, Leishmania infantum, or L donovani. New World leishmaniasis, in turn, occurs in America, and is mostly caused by Leishmania mexicana, Leishmania amazonensis, Leishmania braziliensis, Leishmania panamensis, or Leishmania infantum chagasi (a subspecies of L infantum in the New World, formerly known as Leishmania chagasi).2 The main epidemiological and clinical patterns for most common Leishmania species are shown in Table 1.2–5Fig. 1 shows the geographic distribution of the main species and their principal reservoirs.

Fig. 1.

Geographic distribution of the main Leishmania species and their principal reservoirs.

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In Spain, leishmaniasis is a zoonotic disease endemic to the peninsula and the Balearic Islands. The main causative species in both CL and VL is L infantum, which is transmitted by Phlebotomus perniciosus and Phlebotomus ariasi.6 Dogs are the main reservoir for L infantum, although other reservoirs such as hares7 and rats8 have been described. Apart from its endemic form, leishmaniasis can occur in patients with human immunodeficiency virus (HIV) infection9 or a compromised immune system (e.g., patients being treated with tumor necrosis factor [TNF] inhibitors).10 There have also been epidemic outbreaks, such as the Madrid outbreak that occurred between 2009 and 2013.7 Finally, phenomena such as globalization, international travel, and migration have increased the prevalence of leishmaniasis in developed countries.11

Leishmania promastigotes are injected into human skin by infected female sandflies. Here, through phagocytosis by macrophages, they transform into amastigotes, multiplying inside the cells and infecting other mononuclear phagocytized cells. Sandflies becomes infected by ingesting infected cells while feeding on the host’s blood. Once in the intestine of the sandflies, the amastigotes transform into promastigotes.12 The incubation period of leishmaniasis varies according to the clinical form of disease, but is generally 2 weeks (or less) to 2 months for CL, 3 to 9 months for VL, and over 2 years for MCL.13

The clinical manifestations of leishmaniasis vary according to the species involved14 (Table 1) and the host’s immune response.15 The spectrum of immune response ranges from a strong T-cell response that results in the production of interferon (IFN) γ to a humoral response that produces high antibody levels. Leishmania species are eliminated by IFN-γ-activated macrophages, but cannot be neutralized by antibodies. This is why individuals who mount a strong immune response have lesions with few parasites, while those with a humoral response are unable to control infection. Diffuse CL is caused by uncontrolled infection. It should also be noted that an exaggerated T helper type 1 response and increased expression of CD8+ T cells are associated with more severe forms of disease, such as MCL.15

HIV infection has been linked to a 2000-fold increased risk of VL.33 This is because both infections share a immunopathogenic mechanism involving macrophages and dendritic cells that accelerates progression in both cases.34 HIV was responsible for the resurgence of VL in Europe during the 1990s that hit Spain, Portugal, Italy, and France particularly hard.33,35 Eighty percent of all cases of VL-HIV coinfection reported to the WHO during this period were from Spain.36 In addition, a retrospective analysis of all patients hospitalized for leishmaniasis in Spain between 1997 and 2008 found that 37% were HIV positive.37 Coinfection can result in atypical presentations of CL and VL,18,38,39 poor response to treatment, higher mortality rates, higher viral loads, and faster progression to AIDS. The introduction of highly active antiretroviral therapy in 1997 increased survival rates and also reduced the incidence and recurrence of leishmaniasis.33 It is important thus to rule out HIV in all patients with VL, even those living in endemic areas.3

TNF inhibitors are widely used to treat inflammatory diseases such as psoriasis and rheumatoid arthritis. TNF-α participates in cell-mediated immune response by activating CD4+ and CD8+ T cells. Together with other cytokines such as interleukin 12 and IFN-γ, it has a key role in early infection control. Parasite DNA has been detected in the blood of up to 58% of healthy individuals in the Mediterranean, an endemic area with high levels of exposure to Leishmania, but the actual numbers of people who develop the disease are low.40 It is therefore believed that most immunocompetent individuals are able to control infection before it manifests. Likewise, it has been suggested that TNF-α inhibitors could favor the reactivation of latent leishmaniasis,10 and also modify clinical presentation, the natural course of disease, and response to treatment. Based on the cases published to date, the best approach to dealing with reactivation of a latent infection would appear to be to treat the infection with systemic therapy and interrupt TNF inhibitor treatment until the infection has cleared10; the treatment should then be reintroduced with close follow-up. Etanercept and certolizumab appear to be associated with a lower risk of reactivation than adalimumab or infliximab.41

Leishmaniasis is diagnosed by demonstrating the presence of Leishmania amastigotes in clinical specimens using direct microscopic examination or molecular analysis based on nuclear or kinetoplast DNA amplification. Amastigotes are round and have a diameter of 1 to 4 μm and a characteristic rod-shaped structure known as a kinetoplast. The main sampling and diagnostic techniques are summarized in Table 2.42–45 Considering the limited sensitivity of some of the diagnostic techniques, it may be necessary to take several samples and/or use a combination of techniques to reach a diagnosis. In the case of biopsy specimens, for example, one part could be used for histology, another for touch imprint cytology, and another for culture. Diagnostic sensitivity in VL varies according to tissue type and can be as high as 90% for spleen tissue. Spleen aspiration is the procedure of choice for diagnosing VL, but it is associated with a high risk of intra-abdominal bleeding. Sensitivity rates ranging from 50% to 85% have been reported for bone marrow samples, and even lower rates have been described for lymph node and peripheral blood.46 In PKDL, diagnostic sensitivity using smears or biopsy specimens is largely dependent on the type of lesion analyzed, with rates of up to 100% for nodular lesions contrasting with very low rates for macular lesions,47 where more sensitive molecular methods are needed.48 More information on sampling methods and diagnostic techniques can be consulted in the guidelines of the Centers for Disease Control and Prevention49 and the Infectious Diseases Society of America.50

Histology can show nonspecific features such as ulceration, pseudoepitheliomatous hyperplasia, and a mixed inflammatory infiltrate, as well as specific features, such as amastigotes in dermal macrophages, seen in 50% to 70% of cases43 (Fig. 4). As lesions develop, there is an increase in the number of giant cells and a decrease in that of parasites. Other findings include tuberculoid granulomas,51 and in advanced stages, dermal fibrosis and abundant plasma cells.52 Four histologic patterns have been described for leishmaniasis: 1) abundant amastigotes (45%); 2) a mixture of macrophages, neutrophils, and plasma cells accompanied by necrosis (27.5%); 3) incipient granulomas with epithelioid cells, lymphocytes, and plasma cells (15%); and 4) fully formed epithelioid granulomas with Langhans-type giant cells.53 Histologic findings are similar in CL and MCL. A diffuse infiltrate of macrophages containing large numbers of amastigotes is seen in diffuse CL.52

Fig. 4.

A, Panoramic punch biopsy of an erythematous nodule on the forearm (hematoxylin-eosin, original magnification ×5). B, Dense superficial dermal inflammatory infiltrate and pseudoepitheliomatous hyperplasia (hematoxylin-eosin, original magnification ×10). C, Detail of inflammatory infiltrate composed mainly of macrophages, lymphocytes, and some epithelioid cells (hematoxylin-eosin, original magnification ×20). D, Characteristic amastigotes in infected macrophages (hematoxylin-eosin, original magnification ×40).

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Dermoscopy is another useful diagnostic aid.54 The most frequently described dermoscopic structures are erythema (100%); vascular structures (90.6%), including polymorphous (40.2%), hairpin (39.4%), and arborizing vessels (38.6%); crusts (70.1%); and erosion/ulceration (44.1%). Less common but more characteristic structures are white-yellow teardrop-like structures (42.5%) and the white starburst pattern (8.6%)55 (Fig. 2F).

Other tests, which are less useful in the diagnosis of CL, are the Montenegro skin test and serological tests. The former consists of the intradermal injection of leishmanin, and its results are read and interpreted in a similar way to those of the tuberculin test. It is negative in diffuse CL, active VL, and PKDL,56 and cannot differentiate between current and past infection. It is mainly useful for epidemiological purposes.

Serological tests include the direct agglutination test, immunofluorescence, enzyme-linked immunoassay (ELISA), and Western blot analysis. These tests are highly sensitive in VL.57 Antibody titers, however, drop very slowly after cure and the test does not discriminate between active and past infection. Results can also be affected by cross-reactivity with other antibodies (e.g., Chagas disease).58 In addition, asymptomatic individuals in endemic areas often have antibodies, meaning that results have to be carefully interpreted according to the clinical context. High levels of anti-α-galactosyl antibodies have been detected using ELISA in CL caused by L tropica and L major.59 A number of rapid diagnostic tests, such as rK39, are also available. These have high sensitivity for VL,60 but they have the same limitations as other serological tests. More recent antigen detection tests include the latex agglutination test61 and ELISA62 with urine samples in VL and an immunochromatographic strip that tests for peroxidoxin antigen63 in CL.

The main entities that should be considered in the differential diagnosis are other infections, such as ecthyma, sporotrichosis, skin tuberculosis, furuncular myasis, subcutaneous mycosis, tertiary syphilis, and lepromatous leprosy; malignancies, such as squamous cell carcinoma, basal cell carcinoma, and lymphoma; and other skin disorders, such as persistent arthropod bite reactions, sarcoidosis, and granulomatosis with polyangitis.43

Many cases of CL resolve spontaneously in under 2 years. Variations in resolution times are largely related to the species involved (Table 1), with infections caused by L braziliensis and L panamensis most likely to persist.64 Depending on this and other factors, such as anatomic location, infection severity, and the host’s immune response, CL can be classified as simple or complex. Simple infections can be treated conservatively or with local treatments, while complex infections require systemic therapies.50 The characteristics of simple and complex CL are summarized in Table 3. Multiple treatments exist for leishmaniasis, although the evidence supporting the options for CL is weak.65 The main treatments are shown in Table 4.66–97

After weighing up the risks and benefits, a watch-and-wait approach can be taken in patients who meet the criteria for simple CL. Local treatment can be used for lesions that do not resolve spontaneously or when the goal is to achieve a faster cure or reduce the risk of scarring. The most widely accepted local treatments are intralesional pentavalent antimonials66–69 and cryotherapy.76 The combination of both produces better outcomes.70,71 Topical paromomycin is also used to treat CL, particularly in the New World.73–75

There have been reports of good responses to other local treatments,98 such as carbon dioxide laser therapy,99 which has shown efficacy rates of 93% and very few adverse effects (hyperpigmentation, persistent erythema, and hypertrophic scarring); photodynamic therapy80; and imiquimod.100

Systemic therapies are recommended for patients who meet any of the criteria for complex CL. Liposomal amphotericin B is highly effective but carries a risk of nephrotoxicity.89–93 The traditional use of systemic pentavalent antimonials85–88 to treat complex CL and MCL has led to resistance in certain areas, limiting their use.87 Other options include azoles,81 miltefosine,82–84 and pentamidine.94–96

A clinical trial comparing twice-daily chloroquine 250 mg and once-daily doxycycline 200 mg for 3 months reported an efficacy of 100% and 92%, respectively.101

Annual check-ups are recommended in patients with CL due to L braziliensis to enable early detection of progression to MCL. Signs of MCL include persistent nasal secretion or bleeding.

PKDL from Africa is not normally treated as the vast majority of cases (85%) resolve spontaneously within a year. In India, however, systemic treatment with miltefosine or amphotericin B is generally needed.1

We have drawn up an algorithm for the management of CL and MCL based on current guidelines and expert recommendations (Fig. 5).

Fig. 5.

Treatment algorithm for cutaneous and mucocutaneous leishmaniasis. IL indicates intralesional; IM, intramuscular; IV, intravenous; PDT, photodynamic therapy; VO, oral. * foreign medication.

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Prophylactic vaccines for leishmaniasis in humans are not yet available. The fact that most patients who recover from leishmaniasis do not become reinfected facilitates vaccine research efforts.102 One of the main control strategies for CL and VL, apart from vector control, involves early detection and treatment, as infected patients are reservoirs. The WHO’s target for CL in the eastern Mediterranean region was to detect 70% of all cases and to treat at least 90% by 2020, an ambitious target considering the few treatment options available, the suboptimal diagnostic tools, and the low levels of awareness among the scientific community, particularly in relation to CL, which is not classified as an infection control priority.

CL has become a relatively common condition in our setting due to international travel and migration. Its management, however, can be complicated due to low indices of suspicion among clinicians, the low sensitivity of some diagnostic tests, poor access to molecular testing, limited treatment options, and adverse treatment effects. HIV coinfection and use of TNF inhibitors are associated with atypical presentations and the need for systemic treatment.

The authors declare that they have no conflicts of interest.