Are You Confident of the Diagnosis?
Leishmaniasis is a vector-borne protozoan infection transmitted by the sandfly. Numerous Leishmania species are responsible for disease and may cause either visceral leishmaniasis (VL) or cutaneous leishmaniasis (CL). VL is a serious systemic infection which, if untreated, is fatal. It is clinically distinct from CL, presenting with hepatosplenomegaly and severe cachexia. This chapter focuses on CL and its clinical subtypes. Although rarely fatal, CL is disfiguring; the severe clinical variants can be associated with significant morbidity, and it may be poorly responsive to treatment.
What to be alert for in the history
Patients will have travelled to an endemic region for CL. They often do not recall the bite of the sandfly. Incubation periods are highly variable, ranging from a few weeks to several months. The initial lesion or lesions may look non-specific and be asymptomatic and therefore may be ignored by the patient or misdiagnosed by the clinician and suspected to be only an insect bite reaction. However, esions will persist and continue to increase in size and change in morphology. Secondary bacterial infection is common and may cause discomfort. There is a tendency for CL lesions to self-limit without treatment, but this varies and depends on the infective Leishmania species.
The self-limiting times of the different Leishmania species are highly variable: L major, L mexicana complex and cutaneous lesions associated with L donovani complex usually self-limit within 3 to 6 months; for L braziliensis complex and L tropica it often takes up to 1 year; and for L aethiopica this may range from 6 months to several years.
Self-limiting lesions often leave scarring. One of the aims of treatment is to reduce the severity and extent of scarring. Even after lesions of CL have resolved there is a risk of relapse in the future or progression to other clinical variants (mucocutaneous leishmaniasis [MCL] or diffuse CL) depending on the infective species and host immune responses. This risk is decreased by effective treatment. Early signs of mucosal disease are nasal stuffiness, which may progress to epistaxis.
Classification of CL
Depending on the clinical history and presentation, CL may be classified as localized CL (LCL), mucocutaneous leishmaniasis (MCL), disseminated leishmaniasis, diffuse leishmaniasis, or lesihmaniasis recidivans. In addition, post-kala-azar-leishmaniasis (PKDL) is a cutaneous sequela of VL.
Characteristic findings on physical examination
There are several clinical variants of CL. By far the most common is LCL. Lesions of LCL usually occur on exposed sites. A variant of LCL endemic in the rainforests of Central and South America is the “chiclero ulcer,” which characteristically affects the pinna only. The initial lesion of LCL may be a non-specific erythematous and indurated patch. This progresses to papular and nodular lesions. Lesions may remain nodular or may ulcerate or become hyperkeratotic depending on the infective Leishmania species.
Ulcerative lesions rarely affect subcutaneous tissue except in the case of chiclero ulcer, which can affect the cartilage of the pinna (Figure 1). It is usually possible to see the active margin of both the ulcerative and hyperkeratotic forms of LCL. The initial papulonodular lesion and active margins of more developed lesions may look granulomatous. Local lymphangitic spread with satellite lesions or sporotrichoid spread may occur. Localized lymphangitis or lymph node enlargement may also occur. Secondary lesions of CL may arise as a result of autoinoculation or Koebner phenomenon, which have been reported to occur after trauma or surgical procedures.
LCL caused by either L major, L mexicana complex or L braziliensis complex is characteristically a well-defined ulcerative lesion with an active, erythematous border (Figure 2). It is often described as a wet lesion although ulcers of L major are often crusted. Chiclero’s ulcer is usually caused by L mexicana complex.
LCL caused by L tropica is characteristically a very hyperkeratotic lesion and an active erythematous border can sometimes be seen. It is often described as a “dry lesion” (Figure 3).
LCL caused by L aethiopica or L donovani complex usually present with papulonodular lesions that are smooth and may look granulomatous.
Complications of LCL include progression to the other more severe but rarer clinical variants of CL, namely MCL, disseminated CL, diffuse CL or leishmaniasis recidivans. The likelihood of this occurring depends on the infective Leishmania species and host cellular immune responses.
MCL usually involves the nasal and buccal mucosae, causing considerable inflammation with risks of necrosis and destruction of oro- and nasopharyngeal/ laryngeal cartilage. Death can occur from respiratory compromise and malnutrition. There is a significant risk of developing
MCL with L braziliensis complex, with estimates of 1% to 10% of patients with LCL due to L braziliensis complex being at risk of progressing to
MCL 1 to 5 years after the initial LCL lesions have healed. In Latin America, this destructive form of MCL is often described as “espundia.”
L aethiopica can also cause a destructive form of MCL, but the magnitude of the risk of developing this is unknown (Figure 4). In MCL the cutaneous lesions often will have already healed, as evidenced by scarring, and only mucosal disease may be active.
Disseminated CL is used to describe the development of multiple lesions occurring in two or more non-contiguous sites on the body. There may be a few or hundreds of lesions. These lesions develop within a few weeks of the initial lesion of LCL from which there has been spread of the Leishmania parasites by the hematogenous and lymphatic routes. The lesions are usually papulonodular but acneiform lesions have also been described. Disseminated CL may also be associated with mucosal disease, the Leishmania parasite presumably disseminating to both the skin and mucosae in such cases.
Disseminated CL can self-limit and usually responds well to treatment. It has been reported most frequently with L braziliensis complex and L mexicana complex.
Diffuse CL is very rare and occurs as an anergic response to Leishmania infection, which produces multiple non-ulcerative papulonodular or infiltrative cutaneous lesions, which may affect any part of the body including the face (and especially the outer aspect of the ears). There may be a few lesions only or hundreds of lesions, and the lesions tend to persist rather than self-limit. Lesions develop much more slowly than in disseminated CL and may present many months or years after the initial lesion of LCL.
Diffuse CL characteristically does not self-limit and responds poorly to treatment. Tests for specific cell-mediated immunity are always negative and lesions are characteristically laden with parasites. It is caused mainly by L amazonensis in Latin America or L aethiopica in East Africa (Figure 5).
Disseminated CL and diffuse CL have distinct clinical, histologic and immunologic profiles but are sometimes erroneously described in the literature as the same entity.
Leishmaniasis recidivans describes the recurrence of CL around the margin of the scar of a previously healed lesion of LCL. Papulonodular and infiltrative lesions develop sometimes many years after clinical cure of the initial lesion of CL. These lesions grow very slowly over many years and because of its clinical and histologic similarities with lupus vulgaris, leishmaniasis recidivans has also been known as lupoid leishmaniasis. However, lupoid leishmaniasis has also been used to describe chronic forms of LCL that do not heal spontaneously as expected. Again, clinically and histologically they share features with lupus vulgaris. Leishmaniasis recidivans has most commonly been associated with L tropica.
In PKDL, widespread maculopapular lesions develop following resolution of VL. PKDL affects approximately 5% of patients with VL in East Africa but up to 20% of patients with VL in the Indian subcontinent. Clinical disease is milder and more self-limiting in East Africa. In the Indian subcontinent it may develop long after VL has been cured and persist for a long time, and therefore drug therapy is usually required.
Leishmaniasis is an emerging opportunistic infection in HIV-infected patients. It has been a significant problem with VL co-infection, and these patients have shown poor responses to systemic chemotherapy and high relapse rates, although relapse has been reduced by HAART and secondary prophylaxis. A similar clinical picture is emerging with HIV co-infection with CL. HIV co-infection is associated with rapid progression of CL, an increased risk of atypical and severe lesions of CL, which have a reduced tendency to self-limit, and an increased tendency for Leishmania parasites to disseminate.
There have been reports of disease progression to MCL and diffuse CL and also of visceral involvement. HIV-infected patients characteristically show poor responses to standard therapies for CL and higher rates of disease relapse.
The differential diagnosis of CL is broad because of its diverse clinical presentations. Very early lesions may be confused with insect bites or pyoderma, the latter especially when there is secondary bacterial infection of CL lesions. Because lesions of CL may look granulomatous they may be confused with sarcoidosis (particularly the papulonodular non-ulcerative and non-hyperkeratotic variants) or cutaneous infections such as tuberculosis (leishmaniasis recidivans or hyperkeratotic LCL mimicking lupus vulgaris or tuberculosis verrucosa cutis respectively).
In chronic nodular or chronic ulcerative lesions, squamous cell or basal cell carcinomas or cutaneous lymphomas may be suspected. In sporotrichoid forms of CL, other infections such as sporotrichosis or Mycobacterium marinum infection need to be considered. Diffuse CL is often confused with lepromatous leprosy in endemic regions. In patients from Latin America, paracoccidiodomycosis must be considered in cases of centrofacial mucocutaneous lesions.
Expected results of diagnostic studies
Traditionally, CL has been diagnosed microscopically by the identification of amastigotes within macrophages in biopsies, scrapings or impression smears of skin or mucosal lesions. Species identification is critical as it determines the clinical course, prognosis and treatment choice, and until the recent development of molecular methods it was only possible through isoenzyme analysis of Leishmania culture. However, the sensitivity of microscopy and culture has tended to be low and is highly variable. Culture may also take up to 4 weeks. Polymerase chain reaction (PCR) technology now enables rapid detection of Leishmania-specific DNA, demonstrating 100% specificity and very high sensitivity.
If CL is suspected, ideally four investigations should be performed to maximize sensitivity and specificity: direct microscopy, culture, histopathology and PCR. Tissue samples can be obtained in a variety of ways: simple aspiration, scrapings, slit incisions or skin biopsy. However, biopsy specimens are preferred as they enable all tests to be performed; they can be used to prepare impression smears for direct microscopy and inoculated for culture. The biopsy should be taken from the active edge of skin lesions rather than from the center or the base of an ulcer.
Recent skin lesions give a higher parasite yield. Studies of the histopathology of CL have demonstrated that the presence of amastigotes (Leishmania parasites within macrophages) is inversely related to the size and duration of lesions. Therefore, failure to visualize amastigotes on histopathology does not exclude the diagnosis, and this is why all of the above tests should be performed.
Who is at Risk for Developing this Disease?
CL is endemic in more than 80 countries throughout Africa, Asia, southern Europe (Old World) and Latin America (New World). It has an estimated prevalence of 12 million cases worldwide, and this continues to increase with 1.5 to 2 million new cases each year. New foci of leishmaniasis are emerging as a result of changes to ecology and sandfly habitats due to deforestation, urbanization, and civil conflict.
There has also been spread to previous non-endemic regions such as the state of Texas in the United States. Ninety percent of cases of CL occur in Afghanistan, Algeria, Brazil, Pakistan, Peru, Saudi Arabia and Syria. It is normally a zoonotic disease with a number of mammalian reservoirs, but it can also be an anthroponotic disease (ie, humans are the main reservoir host), particularly in urban environments where it may occur as epidemics and constitute a significant public health problem.
What is the Cause of the Disease?
Disease expression depends upon a number of factors: Leishmania species, size of Leishmania inoculum, sandfly saliva (has vasodilatory properties) and other vector virulence factors, and host cellular immune responses. The Leishmania species determines the clinical outcome: CL, MCL or VL.
More than 20 Leishmania protozoa species are responsible for disease in humans.
L major and L tropica are the predominant species causing Old World CL, which usually produces localized disease only. L tropica is the principal species responsible for anthroponotic infection. L aethiopica, which is restricted to Ethiopia and the highlands of Kenya, most commonly presents with LCL but can also cause the severe mucocutaneous and diffuse variants.
L mexicana complex and L braziliensis complex are responsible for New World CL. L mexicana complex usually causes self-limiting LCL. However, L braziliensis complex (Viannia subgenus), which can also cause a self-limiting LCL, is associated with a significant risk of disease progression to MCL. Both L mexicana complex and L braziliensis complex may rarely cause diffuse CL, particularly L amazonensis. The L donovani complex is responsible for VL but occasionally produces localized self-limiting cutaneous lesions (Table I).
|CL||OWNW||L majorL tropicaL aethiopicaL mexicana complexL mexicanaL amazonensisL venezuelensis|
|CL/MCL||OWNW||L aethiopicaL braziliensis complexL (Viannia) braziliensisL (Viannia) colombiensisL (Viannia) guyanensisL (Viannia) panamensisL (Viannia) peruviana|
|VL/CL||OWNW||L donovani complexL donovaniL infantumL donovani complexL chagasi|
OW: Old World
NW: New World
The immune response to Leishmania infection is cell-mediated and the clinical outcome depends on host-mediated T helper (Th) 1 or Th 2 responses. A Th1 response mediated by interferon (INF)-γ, interleukin (IL)-12 and tumor necrosis factor (TNF) is associated with disease resolution and resistance, and a Th2 IL-4-producing response confers disease susceptibility and progression. These immune responses account for the diverse clinical spectrum of CL: Localized self-healing lesions demonstrate a predominantly Th1 cytokine profile while Th2-mediated responses characterize diffuse, disseminated, and non-healing lesions; MCL demonstrates a mixed Th1 and Th2 response, which may account for both its aggressive inflammatory activity and chronicity.
Systemic Implications and Complications
Leishmania species responsible for CL and its different clinical subtypes very rarely can affect internal organs. Visceralization of dermatrophic Leishmania species has been described in a few case reports in patients who are immunosuppressed, usually with HIV co-infection.
Treatment options for CL re summarized in Table II.
|Treatment Regimen||Species||Adverse effects|
|Intralesional antimonial||Weekly therapy until cure||L majorL tropicaL mexicana complex||Pain at injection site|
|Cryotherapy||Weekly treatment of two freeze/thaw cycles for 10 to 25 seconds until cure||L majorL tropicaL mexicana complex||Risk of secondary infectionPigmentary change|
|Thermotherapy||1 to 3 applications of radiofrequency waves at 50°C for 30 seconds||L tropicaL mexicana complex||Risk of secondary infection|
|Topical paromomycin in 10% urea or 12% methylbenzethonium chloride||Twice daily application for up to 4 weeks||L majorL mexicana complex||Local irritation|
|Miltefosine||2.5mg/kg/day for 28 days||Efficacy for most species, both OW & NW||Gastrointestional disturbance, Teratogenic|
|Fluconazole||200mg daily for 6 weeks||L major||Hepatotoxic|
|Ketoconazole||600mg daily for 4 to 6 weeks||L mexicana complex||Hepatotoxic|
|Antimonials (sodium stibogluconate or meglumine antimoniate)||20mg/kg/day for 20 to 28 days||L braziliensis complex||Cardiotoxic, hepatoxic, nephrotoxic|
|Pentamidine isethionate||Usually 3 doses on alternate days at 2 to 4mg/kg||L braziliensis complexL aethiopica||Glucose intolerance|
|Amphotericin||Second-line agent for severe infection.Several regimens used (total dose <1.5 to 2g)||L braziliensis complex||Nephrotoxic|
OW: Old World
NW: New World
Optimal Therapeutic Approach for this Disease
The goal of treatment is to accelerate healing, reduce the risk of scarring (especially in cosmetic sites), prevent the risk of complications and spread of infection (in the case of anthroponotic transmission in endemic regions). The choice of treatment depends on the size and location
of the lesion, the number of lesions, the potential for the Leishmania species to disseminate to the mucosae or other sites, and host co-morbidities.
Before treatment initiation it is important to try to establish the causative species especially for LCL as this will determine the future risk of complications. ther host co-morbidities, particularly HIV status and other causes of immunosuppression, need to be ascertained as this will determine responses to standard treatment.
LCL caused by Leishmania species that do not have the potential to cause the more serious variants may be treated with local forms of therapy that have no associated risks of toxicity. LCL due to Leishmania species that have the potential to disseminate should be treated with systemic therapy: however, the risks of disease progression should be balanced against the risks associated with drug toxicity.
Systemic drugs demonstrate considerably greater efficacy in the treatment of LCL than diffuse CL or MCL caused by the same Leishmania species. Diffuse CL and MCL characteristically demonstrate poor or partial responses and high rates of relapse with currently available treatments, and there is a need for new therapies to treat these more severe variants of CL. This is because in addition to drug therapy, host immune responses are important for Leishmania parasite eradication, and the immunologic disease profile of these clinical variants differs.
The poor treatment responses of diffuse CL and MCL need to be taken into account in the choice of treatment for LCL caused by Leishmania species with the potential to progress to these variants.
Treatment of LCL with local therapy is only possible for solitary or few lesions that are not too large and are amenable to treatment: The location of the lesions is important as they cannot always be treated if the lesions are in awkward areas such as near the eyes or on the nose, in which case systemic treatments may be preferred.
Lesions over cartilage, joints or lower legs have a tendency to heal poorly. Therefore, even if the causative Leishmania species does not have the potential to disseminate, the clinician may choose to treat these lesions with systemic therapy rather than local therapy. Cases of CL with HIV co-infection or other states of immunosuppression usually require systemic therapy irrespective of Leishmania species to ensure complete cure and to prevent any risk of relapse.
Of the local therapies, intralesional antimonials are often associated with the highest rates of success in the treatment of LCL but require effective technique. Lesions should be infiltrated at the base. The number of treatments required varies considerably, depending on lesion size and morphology.
Cryotherapy is often chosen as an alternative to intralesional antimonials but is not always a suitable option for ulcerative lesions. In pigmented skin it may cause disfiguring hypopigmentation although if this is mild it usually successfully repigments over time.
The efficacy of topical paromomycin (an aminoglycoside antibiotic) has often been questioned by clinicians as trials demonstrating its efficacy were carried out for LCL caused by Leishmania speciesthat have relatively short self-resolution times. Hence, it is difficult to demonstrate a significantly shorter time to disease resolution with therapy than without. Since secondary bacterial infection is common in CL, it is possible that any improvement may be attributable to paromomycin’s anti-bacterial effects. Local forms of therapy may be combined to increase efficacy. Topical paromomycin may be combined with intralesional antimonials.
Of the systemic drugs, the azoles are generally considered to be the least effective: Data supporting their efficacy come from trials involving Leishmania species with relatively short self-resolution times. However, of the systemic drugs used in the treatment of CL, azoles are also associated with the lowest risks of toxicity.
The major limitation of the parenteral treatments is that their route of drug administration is inconvenient. In addition, they are associated with toxicity, particularly with long courses of treatment. Of the three parenteral treatments listed in the table, there is the greatest amount of trial data for antimonials, making them the gold standard for the treatment of most cases of CL requiring systemic therapy.
There is growing interest in miltefosine as it is an oral drug that can be self-administered by the patient and is associated with relatively less toxicity than the other systemic drugs for treating CL. There is now trial data demonstrating its efficacy for most Leishmania species although efficacy rates vary according to Leishmania species and geographic region.
There is no contraindication to patients who require systemic drug therapy also having local forms of therapy to selected lesions to speed up the time of disease resolution.
Treatment should be continued until there is clinical disease resolution, ie, lesions have healed leaving scarring and there is no evidence of skin induration, which may suggest continued disease activity. Clinicians may choose to corroborate apparent clinical cure by confirming parasitologic cure as well. This is done by repeating skin smears and other diagnostic tests. Skin smears usually leave less scarring than punch biopsies.
In the case of Leishmania species that have the potential to disseminate or in the case of host immunocompromised states (eg, HIV co-infection), the clinician may choose to continue with systemic drug therapy for a period after clinical and/or parasitologic cure to minimize any risk of disease progression or relapse.
After effective clinical and parasitologic cure, patients require follow-up to ensure that there is no recurrence or progression of disease. Patients infected with Leishmania species with the potential to cause diffuse CL or MCL require longer-term follow-up, as do patients with immunosuppressive states who are at higher risk of relapse irrespective of Leishmania species. At present, no maintenance therapy is recommended for HIV co-infected patients with CL after cure to prevent disease relapse, as is the case with VL.
Unusual Clinical Scenarios to Consider in Patient Management
Non-melanoma skin cancers, including squamous cell carcinomas and basal cell carcinomas, may complicate long-standing scars due to leishmaniasis. However, this is an extremely rare complication.
What is the Evidence?
“Leishmaniasis”. (The WHO site for leishmaniasis has up-to-date information on disease epidemiology for both CL and VL and gives a comprehensive overview of both diseases.)
Ameen, M. “Cutaneous leishmaniasis: therapeutic strategies and future directions”. Expert Opin Pharmacother. vol. 8. 2007. pp. 2689-99. (This review describes the evidence to support the efficacy of established local and systemic therapies used for CL.)
Ameen, M. “Cutaneous and mucocutaneous leishmaniasis: emerging therapies and progress in disease management”. Expert Opin Pharmacother. vol. 11. 2010. pp. 557-69. (This update on therapy options for both CL and MCL presents new data for emerging drugs such as miltefosine and physical therapies such as thermotherapy and photodynamic therapy as well as the potential of immunotherapy as a form of adjuvant therapy to standard chemotherapy.)
Couppie, P, Clyti, E, Sobesky, M, Del Giudice, P, Sainte-Marie, D, Dedet, JP. “Comparative study of cutaneous leishmaniasis in human immunodeficiency virus (HIV)-infected patients and non-HIV-infected patients in French Guiana”. Br J Dermatol. vol. 151. 2004. pp. 1165-71. (An informative article describing the presentation and challenges in management of CL with HIV co-infection.)
Desjeux, P. “Leishmaniasis”. Comp Immunol Microbiol Infect Dis. vol. 27. 2004. pp. 305-18. (Addresses the epidemiology of leishmaniasis and challenges to public health.)
Gonzalez, U, Pinart, M, Reveiz, L, Alvar, J. “Interventions for Old World cutaneous leishmaniasis (Review)”. Cochrane Database Syst Rev. vol. 4. 2008. pp. CD005067(Assessed all randomized controlled trials for CL in the Old World. Although the authors felt many studies were not of a sufficiently high standard, this review provides an overview of the range of treatments that have been used for CL in the Old World.)
Gonzalez, U, Pinart, M, Rengifo-Pardo M Macaya, A, Alvar, J, Tweed, JA. “Interventions for American cutaneous and mucocutaneous leishmaniasis (Review)”. Cochrane Database Syst Rev. vol. 2. 2009. pp. CD004834(Assessed all randomized controlled trials for CL in the New World and pooled analyses where possible. Although many studies were designed and reported poorly, there was good trial data for the treatment of L braziliensis complex infections.)
Reithinger, R, Dujardin, JC. “Molecular diagnosis of leishmaniasis: current status and future applications”. J Clin Microbiol. vol. 45. 2007. pp. 21-5. (The field of molecular diagnostics has considerably improved our management of CL as histopathology is often insufficient and Leishmania species identification determines disease prognosis.)
Murray, HW, Berman, JD, Davies, CR, Saravia, NG. “Advances in leishmaniasis”. Lancet. vol. 366. 2005. pp. 1561-77. (A comprehensive overview of all variants of this infection.)
Wright, NA, Davis, LE, Aftergut, KS, Parish, CA, Cockerell, CJ. “Cutaneous leishmaniasis in Texas : a northern spread of endemic areas”. J Am Acad Dermatol. vol. 58. 2008. pp. 650-2. (This article highlights the worrying trend of new foci of CL appearing in previous non-endemic regions.)
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