Encompassing a complex group of disorders, leishmaniasis is caused by unicellular eukaryotic obligatory intracellular protozoa of the genus Leishmania and primarily affects the host's reticuloendothelial system. Leishmania species produce widely varying clinical syndromes ranging from self-healing cutaneous ulcers to fatal visceral disease. These syndromes fall into three broad categories: visceral leishmaniasis (VL), cutaneous leishmaniasis (CL), and mucosal leishmaniasis (ML).
Leishmaniasis is caused by ∼20 species of the genus Leishmania in the order Kinetoplastida and the family Trypanosomatidae (Table 212-1). Several clinically important species are of the subspecies Viannia. The organisms are transmitted by phlebotomine sandflies of the genus Phlebotomus in the “Old World” (Asia, Africa, and Europe) and the genus Lutzomyia in the “New World” (the Americas). Transmission may be anthroponotic (i.e., the vector transmits the infection from infected humans to healthy humans) or zoonotic (i.e., the vector transmits the infection from an animal reservoir to humans). Human-to-human transmission via shared infected needles has been documented in IV drug users in the Mediterranean region. In utero transmission to the fetus occurs rarely.
Table 212-1 Geographic Distribution and Characteristic Epidemiology of Leishmaniases |Favorite Table|Download (.pdf)
Table 212-1 Geographic Distribution and Characteristic Epidemiology of Leishmaniases
|Organism, Endemic Region||Clinical Syndrome||Species||Vector||Reservoir||Transmission||Setting|
|L. donovani Complex|
|South Asia||VL, PKDL||L. donovani||Phlebotomus argentipes||Humans||Anthroponotic||Rural, domestic|
|Sudan, Somalia, Ethiopia, Kenya, Uganda||VL, PKDL||L. donovani||P. orientalis, P. martini||Humans, rodents in Sudan, canines||Anthroponotic, occasionally zoonotic||Majority peridomestic, occasionally sylvatic|
|Mediterranean basin, Middle East, Central Asia, China||VL, CL||L. infantum||P. perniciosus, P. ariasi||Dogs, foxes, jackals||Zoonotic||Domestic, peridomestic|
|Middle East, Saudi Arabia, Yemen||VL||L. donovani||P. perniciosus, P. ariasi||Dogs, foxes, jackals||Zoonotic||Domestic, peridomestic|
|Central and South America||VL, CL||L. infantum||Lutzomyia longipalpis||Foxes, dogs, opossums||Zoonotic||Domestic, peridomestic, periurban|
|Azerbaijan, Armenia, Georgia, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, Uzbekistan||VL||L. infantum||P. turanicus||Humans, dogs, foxes||Anthroponotic, zoonotic||Domestic|
|Western India to Turkey, parts of North and East Africa||CL, leishmaniasis recidivans||L. tropica||P. sergenti||Humans||Anthroponotic||Urban domestic, peridomestic|
|Western and Central Asia, North and sub-Saharan Africa||CL||L. major||P. papatasi, P. duboscqi||Nile rats, rodents||Zoonotic||Sylvatic, peridomestic|
|Kazakhstan, Turkmenistan, and Uzbekistan||CL||L. major||P. papatasi, P. duboscqi||Gerbils||Zoonotic||Rural|
|Ethiopia, Uganda, Kenya||CL, DCL||L. aethiopica||P. longipes, P. pedifer||Hyraxes||Zoonotic||Sylvatic, peridomestic|
|Peru, Ecuador||CL, ML||L. (V.) peruviana||Lutzomyia verrucarum, L. peruensis||Wild rodents||Zoonotic||Andean Valleys|
|Guyana, Surinam, French Guyana, Ecuador, Brazil, Colombia, Bolivia||CL, ML||L. (V.) guyanensis||L. umbratilis||Sloths, arboreal anteaters, opossums||Zoonotic||Tropical forests|
|Central America, Ecuador, Colombia||CL, ML||L. (V.) panamensis||L. trapidoi||Sloths||Zoonotic||Tropical forest and deforested areas|
|South and Central America||CL, ML||L. (V.) braziliensis||Lutzomyia spp., L. umbratilis, Psychodopygus wellcomei||Forest rodents, peridomestic animals||Zoonotic||Tropical forest and deforested areas|
|L. mexicana Complex|
|Central America and northern parts of South America|
CL, ML, DCL
|Tropical forest and deforested areas|
CL, ML, DCL
Variety of forest rodents and marsupials
|CL, DCL||L. pifanoi||L. olmeca||Variety of forest rodents and marsupials||Zoonotic||Tropical forest and deforested areas|
Leishmania organisms occur in two forms: extracellular, flagellate promastigotes (length, 10–20 μm) in the sandfly vector and intracellular, nonflagellate amastigotes (length, 2–4 μm; Fig. 212-1) in vertebrate hosts, including humans. Promastigotes are introduced through the proboscis of the female sandfly into the skin of the vertebrate host. Neutrophils predominate among the host cells that first encounter and take up promastigotes at the site of parasite delivery. The infected neutrophils may undergo apoptosis and release viable parasites that are taken up by macrophages, or the apoptotic cells may themselves be taken up by macrophages and dendritic cells. The parasites multiply as amastigotes inside macrophages, causing cell rupture with subsequent invasion of other macrophages. While feeding on infected hosts, sandflies pick up amastigotes, which transform into the flagellate form in the flies′ posterior midgut and multiply by binary fission; the promastigotes then migrate to the anterior midgut and can infect a new host when flies take another blood meal.
A macrophage with numerous intracellular amastigotes (2–4 μm) in a Giemsa-stained splenic smear from a patient with visceral leishmaniasis. Each amastigote contains a nucleus and a characteristic kinetoplast consisting of multiple copies of mitochondrial DNA. A few extracellular parasites are also visible.
Leishmaniasis occurs in 98 countries—most of them developing—in tropical and temperate regions (Fig. 212-2). Two million cases occur annually, of which 1–1.5 million are CL (and its variations) and 500,000 are VL. More than 350 million people are at risk, with an overall prevalence of 12 million. Although the distribution of Leishmania is limited by the distribution of sandfly vectors, human leishmaniasis is on the increase worldwide.
Worldwide distribution of human leishmaniasis.
VL (also known as kala-azar, a Hindi term meaning “black fever”) is caused by the L. donovani complex, which includes L. donovani and L. infantum (the latter designated L. chagasi in the New World); these species are responsible for anthroponotic and zoonotic transmission, respectively. India and neighboring Nepal, Bangladesh, Sudan, and Brazil are the four largest foci of VL and account for 90% of the world's VL burden, with India the worst affected. Zoonotic VL is reported from all countries in the Middle East, Pakistan, and other countries from western Asia to China. Endemic foci also exist in the independent states of the former Soviet Union, mainly Georgia and Azerbaijan. In the Horn of Africa, Sudan, Ethiopia, Kenya, Uganda, and Somalia report VL. In Sudan, large outbreaks are thought to be anthroponotic, although zoonotic transmission also occurs. VL is rare in West and sub-Saharan Africa.
Mediterranean VL, long an established endemic disease due to L. infantum, has a large canine reservoir and was seen primarily in infants before the advent of HIV. In Mediterranean Europe, 70% of adult VL cases are associated with HIV co-infection. The combination is deadly because of the impact of the two infections together on the immune system. IV drug users are at particular risk. Other forms of immunosuppression (e.g., that associated with organ transplantation) also predispose to VL. In the Americas, disease caused by L. infantum is endemic from Mexico to Argentina, but 90% of cases in the New World are reported from northeastern Brazil.
The majority of individuals infected by L. donovani or L. infantum mount a successful immune response and control the infection, never developing symptomatic disease. Forty-eight hours after intradermal injection of killed promastigotes, these individuals exhibit delayed-type hypersensitivity (DTH) to leishmanial antigens in the leishmanin skin test (also called the Montenegro skin test). Results in mouse models indicate that the development of acquired resistance to leishmanial infection is controlled by the production of interleukin (IL) 12 by antigen-presenting cells and the subsequent secretion of interferon (IFN) γ, tumor necrosis factor (TNF) α, and other proinflammatory cytokines by the T helper 1 (TH1) subset of T lymphocytes. The immune response in patients developing active VL is complex; in addition to increased production of multiple proinflammatory cytokines and chemokines, patients with active disease have markedly elevated levels of IL-10 in serum as well as enhanced IL-10 mRNA expression in lesional tissues. The main disease-promoting activity of IL-10 in VL may be to condition host macrophages for enhanced survival and growth of the parasite. IL-10 can render macrophages unresponsive to activation signals and inhibit killing of amastigotes by downregulating the production of TNF-α and nitric oxide. Multiple antigen-presentation functions of dendritic cells and macrophages are also suppressed by IL-10. Patients with such suppression do not have positive leishmanin skin tests, nor do their peripheral-blood mononuclear cells respond to leishmanial antigens in vitro. Organs of the reticuloendothelial system are predominantly affected, with remarkable enlargement of the spleen, the liver, and lymph nodes in some regions. The tonsils and intestinal submucosa are also heavily infiltrated with parasites. Bone marrow dysfunction results in pancytopenia.
On the Indian subcontinent and in the Horn of Africa, persons of all ages are affected by VL. In endemic areas of the Americas and the Mediterranean basin, immunocompetent infants and small children and immunodeficient adults are affected especially often. The most common presentation of VL is an abrupt onset of moderate- to high-grade fever associated with rigor and chills. Fever may continue for several weeks with decreasing intensity, and the patient may become afebrile for a short period before experiencing another bout of fever. The spleen may be palpable by the second week of illness and, depending on the duration of illness, may become hugely enlarged (Fig. 212-3). Hepatomegaly (usually moderate in degree) soon follows. Lymphadenopathy is common in most endemic regions of the world except the Indian subcontinent, where it is rare. Patients lose weight and feel weak, and the skin gradually develops dark discoloration due to hyperpigmentation that is most easily seen in brown-skinned individuals. In advanced illness, hypoalbuminemia may manifest as pedal edema and ascites. Anemia appears early and may become severe enough to cause congestive heart failure. Epistaxis, retinal hemorrhages, and gastrointestinal bleeding are associated with thrombocytopenia. Secondary infections such as measles, pneumonia, tuberculosis, bacillary or amebic dysentery, and gastroenteritis are common. Herpes zoster, chickenpox, boils in the skin, and scabies may also occur. Untreated, the disease is fatal in most patients, including 100% of those with HIV co-infection.
A patient with visceral leishmaniasis has a hugely enlarged spleen visible through the surface of the abdomen. Splenomegaly is the most important feature of visceral leishmaniasis.
Leukopenia and anemia occur early and are followed by thrombocytopenia. There is a marked polyclonal increase in serum immunoglobulins. Serum levels of hepatic aminotransferases are raised in a significant proportion of patients, and serum bilirubin levels are elevated occasionally. Renal dysfunction is uncommon.
Demonstration of amastigotes in smears of tissue aspirates is the gold standard for the diagnosis of VL (Fig. 212-1). The sensitivity of splenic smears is >95%, whereas smears of bone marrow (60–85%) and lymph node aspirates (50%) are less sensitive. Culture of tissue aspirates increases sensitivity. Splenic aspiration is invasive and may be dangerous in untrained hands. Several serologic techniques are currently used to detect antibodies to Leishmania. An enzyme-linked immunosorbent assay (ELISA) and the indirect immunofluorescent antibody test (IFAT) are used in sophisticated laboratories. In the field, however, a rapid immunochromatographic test based on the detection of antibodies to a recombinant antigen (rK39) consisting of 39 amino acids conserved in the kinesin region of L. infantum is used worldwide. The test requires only a drop of fingerprick blood or serum, and the result can be read within 15 minutes. Except in East Africa (where both its sensitivity and its specificity are lower), the sensitivity of the rK39 rapid diagnostic test in immunocompetent individuals is ∼98% and its specificity is 90%. Qualitative detection of leishmanial nucleic acid by polymerase chain reaction (PCR) and quantitative detection by real-time PCR are confined to specialized laboratories and have yet to be used for routine diagnosis of VL in endemic areas. PCR can distinguish among the major species of Leishmania infecting humans.
VL is easily mistaken for malaria. Other febrile illnesses that may mimic VL include typhoid fever, tuberculosis, brucellosis, schistosomiasis, and histoplasmosis. Splenomegaly due to portal hypertension, chronic myeloid leukemia, tropical splenomegaly syndrome, and (in Africa) schistosomiasis may also be confused with VL. Fever with neutropenia or pancytopenia in patients from an endemic region strongly suggests a diagnosis of VL; hypergammaglobulinemia in patients with long-standing illness strengthens the diagnosis. In nonendemic countries, a careful travel history is essential when any patient presents with fever.
Treatment: Visceral Leishmaniasis
Severe anemia should be corrected by blood transfusion, and other comorbid conditions should be managed promptly. Treatment of VL is complex, as the optimal drug, dosage, and duration vary with the endemic region. In spite of completing recommended treatment, some patients experience relapse (most often within 6 months), and prolonged follow-up is recommended. A pentavalent antimonial is the drug of choice in most endemic regions of the world, but there is widespread resistance to antimony in the Indian state of Bihar, where either amphotericin B (AmB) deoxycholate or miltefosine is preferred. Dose requirements for AmB are lower in India than in the Americas, Africa, or the Mediterranean region. In Mediterranean countries, where cost is seldom an issue, liposomal AmB is the drug of choice. In immunocompetent patients, relapses are uncommon with AmB in its deoxycholate and lipid formulations. Antileishmanial therapy has recently evolved as new drugs and delivery systems have become available and resistance to antimonial compounds has emerged.
Except for AmB (deoxycholate and lipid formulations), antileishmanial drugs are available in the United States only from the Centers for Disease Control and Prevention.
Pentavalent Antimonial Compounds
Two pentavalent antimonial (SbV) preparations are available: sodium stibogluconate (100 mg of SbV/mL) and meglumine antimonate (85 mg of SbV/mL). The daily dose is 20 mg/kg by rapid IV infusion or IM injection, and therapy continues for 28–30 days. Cure rates exceed 90% in Africa, the Americas, and most of the Old World but are <50% in Bihar, India, as a result of resistance. Adverse reactions to SbV treatment are common and include arthralgia, myalgia, and elevated serum levels of aminotransferases. Electrocardiographic changes are common. Concave ST segment elevation is not significant, but prolongation of QTc to >0.5 s may herald ventricular arrhythmia and sudden death. Chemical pancreatitis is common but usually does not require discontinuation of treatment; severe clinical pancreatitis occurs in immunosuppressed patients.
AmB is currently used as a first-line drug in Bihar. In others parts of the world, it is used when initial antimonial treatment fails. Conventional AmB deoxycholate is administered in doses of 0.75–1.0 mg/kg on alternate days for a total of 15 infusions. Fever with chills is an almost universal adverse reaction to AmB infusions. Nausea and vomiting are also common, as is thrombophlebitis in the infused veins. Acute toxicities can be minimized by administration of antihistamines like chlorpheniramine and antipyretic agents like acetaminophen before each infusion. AmB can cause renal dysfunction and hypokalemia and in rare instances elicits hypersensitivity reactions, bone marrow suppression, and myocarditis, all of which can be fatal.
The several lipid formulations of AmB developed to replace the deoxycholate formulation are preferentially taken up by reticuloendothelial tissues. Because very little free drug is available to cause toxicity, a large amount of drug can be delivered over a short period. Liposomal AmB has been used extensively to treat VL in all parts of the world. With a terminal half-life of ∼150 h, liposomal AmB can be detected in the liver and spleen of animals for several weeks after a single dose. This is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of VL; the regimen is 3 mg/kg daily on days 1–5, 14, and 21 (total dose, 21 mg/kg). However, the total dose requirement for different regions of the world varies widely. In Asia, it is 10–15 mg/kg; in Africa, ∼18 mg/kg; and in Mediterranean/American regions, not less than 20 mg/kg. The daily dose is flexible (1–10 mg/kg). In a study in India, a single dose of 10 mg/kg cured infection in 96% of patients. Adverse effects of liposomal AmB are usually mild and include infusion reactions, backache, and occasional reversible nephrotoxicity.
Paromomycin (aminosidine) is an aminocyclitol-aminoglycoside antibiotic with antileishmanial activity. Its mechanism of action against Leishmania has yet to be established. Paromomycin is approved in India for the treatment of VL at an IM dose of 11 mg of base/kg daily for 21 days; this regimen produces a cure rate of 95%. However, the optimal dose has not been established in other endemic regions. Paromomycin is a relatively safe drug, but some patients develop hepatotoxicity, reversible ototoxicity, and (in rare instances) nephrotoxicity and tetany.
Miltefosine, an alkylphosphocholine, is the first oral compound approved for the treatment of leishmaniasis. This drug has a long half-life (150–200 h); its mechanism of action is not clearly understood. The recommended therapeutic regimens for patients on the Indian subcontinent are a daily dose of 50 mg for 28 days for patients weighing <25 kg, a twice-daily dose of 50 mg for 28 days for patients weighing ≥25 kg, and 2.5 mg/kg for 28 days for children 2–11 years of age. These regimens result in a cure rate of 94% in India. Doses in other regions remain to be established. Because of its long half-life, miltefosine is prone to induce resistance in Leishmania. Its adverse effects include mild to moderate vomiting and diarrhea in 40% and 20% of patients, respectively; these reactions usually clear spontaneously after a few days. Rare cases of severe allergic dermatitis, hepatotoxicity, and nephrotoxicity have been reported. Because miltefosine is expensive and is associated with significant adverse events, it is best administered as directly observed therapy to ensure completion of treatment and to minimize the risk of resistance induction. Because miltefosine is teratogenic in rats, its use is contraindicated during pregnancy and (unless contraceptive measures are strictly adhered to for at least 3 months after treatment) in women of childbearing age.
Multidrug therapy for leishmaniasis is likely to be preferred in the future. Its potential advantages in VL include (1) better compliance and lower costs associated with shorter treatment courses and decreased hospitalization, (2) less toxicity due to lower drug doses and/or shorter duration of treatment, and (3) a reduced likelihood that resistance to either agent will develop. Trials of multidrug therapy are under way in Asia and Africa.
Prognosis of Treated VL Patients
Recovery from VL is quick. Within a week of the start of treatment, defervescence, regression of splenomegaly, weight gain, and recovery of hematologicparameters are evident. With effective treatment, no parasites are recovered from tissue aspirates at the posttreatment evaluation. Continued clinical improvement over 6–12 months is suggestive of cure. A small percentage of patients (with the exact figure depending on the regimen used) relapse but respond well to treatment with AmB deoxycholate or lipid formulations.
VL in the Immunocompromised Host
HIV/VL co-infection has been reported from 35 countries. VL behaves as an opportunistic infection in HIV-1-infected patients where both infections are endemic. HIV infection can increase the risk of developing VL severalfold in endemic areas. Co-infected patients usually show the classic signs of VL, but they may present with atypical features due to loss of immunity and involvement of unusual anatomic locations, with, for example, infiltration of the skin, oral mucosa, gastrointestinal tract, lungs, and other organs. Serodiagnostic tests are commonly negative. Parasites can be recovered from unusual sites such as bronchoalveolar lavage fluid and buffy coat. Liposomal AmB is the drug of choice for HIV/VL co-infection—both for primary treatment and for treatment of relapses. A total dose of 40 mg/kg, administered as 4 mg/kg on days 1–5, 10, 17, 24, 31, and 38, is considered optimal and is approved by the FDA, but most patients relapse within 1 year. Pentavalent antimonials and AmB deoxycholate can also be used where liposomal AmB is not accessible. Reconstitution of patients′ immunity by antiretroviral therapy has led to a dramatic decline in the incidence of co-infection in the Mediterranean basin. In contrast, HIV/VL co-infection is on the rise in African and Asian countries. Ethiopia is worst affected: up to 30% of VL patients are also infected with HIV. Since restoration of the CD4+ T cell count to >200/μL does decrease the frequency of relapse, antiretroviral therapy (in addition to antileishmanial therapy) is a cornerstone for the management of HIV/VL co-infection. Secondary prophylaxis with liposomal AmB has been shown to delay relapses, but no regimen has been established as optimal.
Post–Kala-Azar Dermal Leishmaniasis
On the Indian subcontinent and in Sudan and other East African countries, 2–50% of patients develop skin lesions concurrent with or after the cure of VL. Most common are hypopigmented macules, papules, and/or nodules or diffuse infiltration of the skin and sometimes of the oral mucosa. The African and Indian diseases differ in several respects; important features of post–kala-azar dermal leishmaniasis (PKDL) in these two regions are listed in Table 212-2, and disease in an Indian patient is depicted in Fig. 212-4.
Table 212-2 Clinical, Epidemiologic, and Therapeutic Features of Post–Kala-Azar Dermal Leishmaniasis: East Africa and the Indian Subcontinent |Favorite Table|Download (.pdf)
Table 212-2 Clinical, Epidemiologic, and Therapeutic Features of Post–Kala-Azar Dermal Leishmaniasis: East Africa and the Indian Subcontinent
|Feature||East Africa||Indian Subcontinent|
|Most affected country||Sudan||Bangladesh|
|Incidence among patients with VL||∼50%||∼2%|
|Interval between VL and PKDL||During VL to 6 months||6 months to 3 years|
|Age distribution||Mainly children||Any age|
|History of prior VL||Yes||Not necessarily|
|Rashes of PKDL in presence of active VL||Yes||No|
|Treatment with sodium stibogluconate||2–3 months||2–4 months|
|Natural course||Spontaneous cure in majority of patients||Spontaneous cure not reported|
Post–kala-azar dermal leishmaniasis in an Indian patient. Note nodules of varying size involving the entire face. The face is erythematous, and the surface of some of the large nodules is discolored.
In PKDL, parasites are scanty in hypopigmented macules but may be seen and cultured more easily from nodular lesions. Cellular infiltrates are heavier in nodules than in macules. Lymphocytes are the dominant cells; next most common are histiocytes and plasma cells. In about half of cases, epithelioid cells—scattered individually or forming compact granulomas—are seen. The diagnosis is based on history and clinical findings, but rK39 and other serologic tests are positive in most cases. Indian PKDL is treated with pentavalent antimonials for 60–120 days. This prolonged course frequently leads to noncompliance. The alternative—several courses of AmB spread over several months—is expensive and unacceptable for most patients. In East Africa, a majority of patients experience spontaneous healing. In those with persistent lesions, the response to 60 days of treatment with a pentavalent antimonial is good.
CL can be broadly divided into Old World and New World forms. Old World CL caused by L. tropica is anthroponotic and is confined to urban or suburban areas throughout its range. Zoonotic CL is most commonly due to L. major, which naturally parasitizes several species of desert rodents that act as reservoirs over wide areas of the Middle East, Africa, and central and southern Asia. Local outbreaks of human disease are common. Major outbreaks currently affect Afghanistan and Pakistan in association with refugees and population movement. CL is increasingly seen in tourists and military personnel on mission in CL-endemic regions of countries like Afghanistan and Iraq and as a co-infection in HIV-infected patients. L. aethiopica is restricted to the highlands of Ethiopia, Kenya, and Uganda, where it is a natural parasite of hyraxes. New World CL is mainly zoonotic and is most often caused by L. mexicana, L. (V.) panamensis, and L. amazonensis. A wide range of forest animals act as reservoirs, and human infections with these species are predominantly rural. As a result of extensive urbanization and deforestation, L. (V.) braziliensis has adapted to peridomestic and urban animals, and CL due to this organism is increasingly becoming an urban disease. In the United States, a few cases of CL have been acquired indigenously in Texas.
As in VL, the proinflammatory (TH1) response in CL may result in either asymptomatic or subclinical infection. However, in some individuals, the immune response causes ulcerative skin lesions, the majority of which will heal spontaneously, leaving a scar. Healing is usually followed by immunity to reinfection with that species of parasite.
A few days or weeks after the bite of a sandfly, a papule develops and grows into a nodule that ulcerates over some weeks or months. The base of the ulcer, which is usually painless, consists of necrotic tissue and crusted serum, but secondary bacterial infection sometimes occurs. The margins of the ulcer are raised and indurated. Lesions may be single or multiple and vary in size from 0.5 to >3 cm (Fig. 212-5). Lymphatic spread and lymph gland involvement may be palpable and may precede the appearance of the skin lesion. There may be satellite lesions, especially in L. major and L. tropica infections. The lesions usually heal spontaneously after 2–15 months. Lesions due to L. major and L. mexicana tend to heal rapidly, while those due to L. tropica and parasites of subspecies Viannia heal more slowly. In CL caused by L. tropica, new lesions—usually scaly, erythematous papules and nodules—develop in the center or periphery of a healed sore, a condition known as leishmaniasis recidivans. Lesions of L. mexicana and L. (V.) peruviana closely resemble those seen in the Old World; however, lesions on the pinna of the ear are common, chronic, and destructive in the former infections. L. mexicana is responsible for chiclero's ulcer, the so-called self-healing sore of Mexico. CL lesions on exposed body parts (e.g., the face and hands), permanent scar formation, and social stigmatization may cause anxiety and depression and may affect the quality of life of CL patients.
Cutaneous leishmaniasis in a Bolivian child. There are multiple ulcers resulting from several sandfly bites. The edges of the ulcers are raised. (Courtesy of P. Desjeux.)
A typical history (an insect bite followed by the events leading to ulceration) in a resident of or a traveler to an endemic focus strongly suggests CL. Cutaneous tuberculosis, fungal infections, leprosy, sarcoidosis, and malignant ulcers are sometimes mistaken for CL.
Demonstration of amastigotes in material obtained from a lesion remains the diagnostic gold standard. Microscopic examination of slit skin smears, aspirates, or biopsies of the lesion is used for detection of parasites. Culture of smear or biopsy material may yield Leishmania. PCR is more sensitive than microscopy and culture and allows identification of Leishmania to the species level. This information is important in decisions about therapy since responses to treatment can vary with the species. Isoenzyme profiling is used to determine species for research purposes.
Treatment: Cutaneous Leishmaniasis
Although lesions heal spontaneously in the majority of cases, their spread or persistence indicates that treatment may be needed. One or a few small lesions due to “self-healing species” can be treated with topical agents. Systemic treatment is required for lesions over the face, hands, or joints; multiple lesions; large ulcers; lymphatic spread; New World CL with the potential for development of ML; and CL in HIV co-infected patients.
A pentavalent antimonial is the first-line drug for all forms of CL and is used in a dose of 20 mg/kg for 20 days, as for VL. The exceptions to this rule are CL caused by L. (V.) guyanensis, for which pentamidine isethionate is the drug of choice (two injections of 4 mg of salt/kg separated by a 48-h interval), and CL due to L. aethiopica, which responds to paromomycin (16 mg/kg daily) but not to antimonials. Relapses usually respond to a second course of treatment. In Peru, topical imiquimod (5–7.5%) plus parenteral antimonials have been shown to cure CL more rapidly than antimonials alone. Azoles and triazoles have been used with mixed responses in both Old and New World CL but have not been adequately assessed for this indication in clinical trials. In L. major infection, oral fluconazole (200 mg/d for 6 weeks) resulted in a higher rate of cure than placebo (79% vs. 34%) and also cured infection faster. Adverse effects include gastrointestinal symptoms and hepatotoxicity. Ketoconazole (600 mg/d for 28 days) is 76–90% effective in CL due to L. (V.) panamensis and L. mexicana in Panama and Guatemala. Miltefosine has been used in CL in doses of 2.5 mg/kg for 28 days. This agent is effective against L. major infections. In Colombia, where CL is due to L. (V.) panamensis, miltefosine was also effective, with a cure rate of 91%. For L. (V.) braziliensis infections, however, the results with miltefosine are less consistent. Other drugs, such as dapsone, allopurinol, rifampin, azithromycin, and pentoxifylline, have been used either alone or in combinations, but most of the relevant studies have had design limitations that preclude meaningful conclusions.
Small lesions (⩽3 cm in diameter) may conveniently be treated weekly until cure with an intralesional injection of a pentavalent antimonial at a dose adequate to blanch the lesion (0.2–2.0 mL). An ointment containing 15% paromomycin sulfate plus 12% methylbenzonium chloride cures 70% of lesions due to L. major in 20 days and may be suitable for lesions caused by other species. Heat therapy with an FDA-approved radiofrequency generator and cryotherapy with liquid nitrogen have also been used successfully.
Diffuse Cutaneous Leishmaniasis (Dcl)
DCL is a rare form of leishmaniasis caused by L. amazonensis and L. mexicana in South and Central America and by L. aethiopica in Ethiopia and Kenya. DCL is characterized by the lack of a cell-mediated immune response to the parasite, the uncontrolled multiplication of which thus continues unabated. The DTH response is negative, and lymphocytes do not respond to leishmanial antigens in vitro. DCL patients have a polarized immune response with high levels of immunosuppressive cytokines, including IL-10, transforming growth factor (TGF) β, and IL-4, and low concentrations of IFN-γ. Profound immunosuppression leads to widespread cutaneous disease. Lesions may initially be confined to the face or a limb but spread over months or years to other areas of the skin. They may be symmetrically or asymmetrically distributed and include papules, nodules, plaques, and areas of diffuse infiltration. These lesions do not ulcerate. The overlying skin is usually erythematous in pale-skinned patients. The lesions are teeming with parasites, which are therefore easy to recover. DCL does not heal spontaneously and is difficult to treat. If relapse and drug resistance are to be prevented, treatment should be continued for some time after lesions have healed and parasites can no longer be isolated. In the New World, repeated 20-day courses of pentavalent antimonials are given, with an intervening drug-free period of 10 days. Miltefosine has been used for several months with a good initial response. Combinations should be tried. In Ethiopia, a combination of paromomycin (14 mg/kg per day) and sodium stibogluconate (10 mg/kg per day) is effective.
The subgenus Viannia is widespread from the Amazon basin to Paraguay and Costa Rica and is responsible for deep sores and for ML (Table 212-1). In L. (V.) braziliensis infections, cutaneous lesions may be simultaneously accompanied by mucosal spread of the disease or followed by spread years later. ML is caused typically by L. (V.) braziliensis and rarely by L. amazonensis, L. (V.) guyanensis, and L. (V.) panamensis. Young men with chronic lesions of CL are at particular risk. Overall, ∼3% of infected persons develop ML. Not every patient with ML has a history of prior CL. ML is almost entirely confined to the Americas. In rare cases, ML may also be caused by Old World species like L. major, L. infantum, or L. donovani.
Immunopathogenesis and Clinical Features
The immune response is polarized toward a TH1 response, with marked increases of IFN-γ and TNF-α and varying levels of TH2 cytokines (IL-10 and TGF-β). Patients have a stronger DTH response with ML than with CL, and their peripheral-blood mononuclear cells respond strongly to leishmanial antigens. The parasite spreads via the lymphatics or the bloodstream to mucosal tissues of the upper respiratory tract. Intense inflammation leads to destruction, and severe disability ensues. Lesions in or around the nose or mouth (espundia; Fig. 212-6) are the typical presentation of ML. Patients usually provide a history of self-healed CL preceding ML by 1–5 years. Typically, ML presents as nasal stuffiness and bleeding followed by destruction of nasal cartilage, perforation of the nasal septum, and collapse of the nasal bridge. Subsequent involvement of the pharynx and larynx leads to difficulty in swallowing and phonation. The lips, cheeks, and soft palate may also be affected. Secondary bacterial infection is common, and aspiration pneumonia may be fatal. Despite the high degree of TH1 immunity and the strong DTH response, ML does not heal spontaneously.
Mucosal leishmaniasis in a Brazilian patient. There is extensive inflammation around the nose and mouth, destruction of the nasal mucosa, ulceration of the upper lip and nose, and destruction of the nasal septum. (Courtesy of R. Dietz.)
Tissue biopsy is essential for identification of parasites, but the rate of detection is poor unless PCR techniques are used. The strongly positive DTH response fails to distinguish between past and present infection.
Treatment: Mucosal Leishmaniasis
The regimen of choice is a pentavalent antimonial agent administered at a dose of 20 mg of SbV/kg for 30 days. Patients with ML require long-term follow-up with repeated oropharyngeal and nasal examination. With failure of therapy or relapse, patients may receive another course of an antimonial but then become unresponsive, presumably because of resistance in the parasite. In this situation, AmB should be used. An AmB deoxycholate dose totaling 25–45 mg/kg is appropriate. There are no controlled trials of liposomal AmB, but administration of 2–3 mg/kg for 20 days is considered adequate. Miltefosine (2.5 mg/kg for 28 days) cured 71% of ML patients in Bolivia. The more extensive the disease, the worse the prognosis; thus prompt, effective treatment and regular follow-up are essential.
Prevention of Leishmaniasis
No vaccine is available for any form of leishmaniasis. Inoculation with live L. major (“leishmanization”) is practiced in Iran. Anthroponotic leishmaniasis is controlled by case finding, treatment, and vector control with insecticide-impregnated bed nets and curtains and residual insecticide spraying. Control of zoonotic leishmaniasis is more difficult. Use of insecticide-impregnated collars for dogs, treatment of infected domestic dogs, and culling of street dogs are measures that have been used with uncertain efficacy to prevent transmission of L. infantum. Personal prophylaxis with bed nets and repellants may reduce the risk of CL infections in the New World.