Leishmaniasis (Leishmania)

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Chapter 277 Leishmaniasis (Leishmania)

Peter C. Melby

The leishmaniases are a diverse group of diseases caused by intracellular protozoan parasites of the genus Leishmania, which are transmitted by phlebotomine sandflies. Multiple species of Leishmania are known to cause human disease involving the skin and mucosal surfaces and the visceral reticuloendothelial organs. Cutaneous disease is generally mild but may cause cosmetic disfigurement. Mucosal and visceral leishmaniasis is associated with significant morbidity and mortality.

Etiology

Leishmania organisms are members of the Trypanosomatidae family and include 2 subgenera, Leishmania (Leishmania) and Leishmania (Viannia). The parasite is dimorphic, existing as a flagellate promastigote in the insect vector and as an aflagellate amastigote that resides and replicates within mononuclear phagocytes of the vertebrate host. Within the sandfly vector the promastigote changes from a noninfective procyclic form to an infective metacyclic stage. Fundamental to this transition are changes that take place in the terminal polysaccharides of the surface lipophosphoglycan (LPG), which allow forward migration of the infective parasites from the sandfly midgut to the mouth parts and inoculation of the host during a blood meal. Metacyclic LPG also plays an important role in the entry and survival of Leishmania in the mammalian host by conferring complement resistance and by facilitating entry into the macrophage by way of multiple receptors, including complement receptors 1 and 3. Once within the macrophage, the promastigote transforms to an amastigote and resides and replicates within a phagolysosome. The parasite is resistant to the acidic, hostile environment of the macrophage and eventually ruptures the cell and goes on to infect other macrophages. Infected macrophages have a diminished capacity to initiate and respond to an inflammatory response, thus providing a safe haven for the intracellular parasite.

Epidemiology

The leishmaniases are estimated to affect 10-50 million people in endemic tropical and subtropical regions on all continents except Australia and Antarctica. The different forms of the disease are distinct in their causes, epidemiologic characteristics, transmission, and geographic distribution. The leishmaniases may occur sporadically throughout an endemic region or may occur in epidemic focuses. With only rare exceptions, the Leishmania organisms that primarily cause cutaneous disease do not cause visceral disease.

Localized cutaneous leishmaniasis (LCL) in the Old World is caused by L. (Leishmania) major and L. (L.) tropica in North Africa, the Middle East, central Asia, and the Indian subcontinent. L. (L.) aethiopica is a cause of LCL and diffuse cutaneous leishmaniasis (DCL) in Kenya and Ethiopia. Visceral leishmaniasis (VL) in the Old World is caused by L. (L.) donovani in Kenya, Sudan, India, Pakistan, and China and by L. (L.) infantum in the Mediterranean basin, Middle East, and central Asia. L. infantum is also a cause of LCL (without visceral disease) in this same geographic distribution. L. tropica also has been recognized as an uncommon cause of visceral disease in the Middle East and India. In the New World, L. (L.) mexicana causes LCL in a region stretching from southern Texas through Central America. L. (L.) amazonensis, L. (L.) pifanoi, L. (L.) garnhami, and L. (L.) venezuelensis cause LCL in South America, the Amazon basin, and northward. Members of the Viannia subgenus (L. [V.] braziliensis, L. [V.] panamensis, L. [V.] guyanensis, and L. [V.] peruviana) cause LCL from the northern highlands of Argentina northward to Central America. Members of the Viannia subgenus also cause mucosal leishmaniasis (ML) in a similar geographic distribution. VL in the New World is caused by L. (L.) chagasi (now considered to be the same organism as L. infantum), which is distributed from Mexico (rare) through Central and South America. L. infantum/chagasi can also cause LCL in the absence of visceral disease.

The maintenance of Leishmania in most endemic areas is through a zoonotic transmission cycle. In general, the dermotropic strains in both the Old and New Worlds are maintained in rodent reservoirs, and the domestic dog is the usual reservoir for L. infantum/chagasi. The transmission between reservoir and sandfly is highly adapted to the specific ecologic characteristics of the endemic region. Human infections occur when human activities bring them in contact with the zoonotic cycle. Anthroponotic transmission, in which humans are the presumed reservoir, occurs with L. tropica in some urban areas of the Middle East and Central Asia, and with L. donovani in India and Sudan. Congenital transmission of L. donovani or L. infantum/chagasi has been reported.

There is a resurgence of leishmaniasis in long-standing endemic areas as well as in new foci. Tens of thousands of cases of LCL occurred in an outbreak in Kabul, Afghanistan, and severe epidemics with >100,000 deaths from VL have occurred in India and Sudan. VL is most prevalent among the poorest of the poor, with substandard housing contributing to the vector-borne transmission and undernutrition leading to increased host susceptibility. The emergence of the leishmaniases in new areas is the result of (1) movement of a susceptible population into existing endemic areas, usually because of agricultural or industrial development or timber harvesting; (2) increase in vector and/or reservoir populations as a result of agriculture development projects; (3) increase in anthroponotic transmission owing to rapid urbanization in some focuses; and (4) increase in sandfly density resulting from a reduction in vector control programs.

Pathology

Histopathologic analysis of the LCL lesion shows intense chronic granulomatous inflammation involving the epidermis and dermis. Occasionally, neutrophils and even microabscesses can be seen. The lesions of DCL are characterized by dense infiltration with vacuolated macrophages containing abundant amastigotes. ML is characterized by an intense granulomatous reaction with prominent tissue necrosis, which may include adjacent cartilage or bone. In VL there is prominent reticuloendothelial cell hyperplasia in the liver, spleen, bone marrow, and lymph nodes. Amastigotes are abundant in the histiocytes and Kupffer cells. Late in the course of disease, splenic infarcts are common, centrilobular necrosis and fatty infiltration of the liver occur, the normal marrow elements are replaced by parasitized histiocytes, and erythrophagocytosis is present.

Pathogenesis

Cellular immune mechanisms determine resistance or susceptibility to infection with Leishmania. Resistance is mediated by interleukin 12 (IL-12)–driven generation of a T helper 1 (Th1) cell response, with interferon-γ inducing classical macrophage activation and parasite killing. Susceptibility is associated with expansion of IL-4–producing Th2 cells and/or the production of IL-10 and transforming growth factor-β, which are inhibitors of macrophage-mediated parasite killing, and the generation of regulatory T cells and alternatively activated macrophages. Patients with ML exhibit a hyperresponsive cellular immune reaction that may contribute to the prominent tissue destruction seen in this form of the disease. Patients with DCL or active VL demonstrate minimal or absent Leishmania-specific cellular immune responses, but these responses recover after successful therapy.

Within endemic areas, people who have had a subclinical infection can be identified by a positive delayed-type hypersensitivity response to leishmanial antigens (Montenegro skin test). Subclinical infection occurs considerably more frequently than does active cutaneous or visceral disease. Host factors (genetic background, concomitant disease, nutritional status), parasite factors (virulence, size of the inoculum), and possibly vector-specific factors (vector genotype, immunomodulatory salivary constituents) influence the expression as either subclinical infection or active disease. Within endemic areas the prevalence of skin test result positivity increases with age and the incidence of clinical disease decreases with age, indicating that immunity is acquired in the population over time. Individuals with prior active disease or subclinical infection are usually immune to a subsequent clinical infection.

Clinical Manifestations

The different forms of the disease are distinct in their causes, epidemiologic features, transmission, and geographic distribution.

Localized Cutaneous Leishmaniasis

LCL (Oriental sore) can affect individuals of any age, but children are the primary victims in many endemic regions. It may present as 1 or a few papular, nodular, plaquelike, or ulcerative lesions that are usually located on exposed skin, such as the face and extremities (Fig. 277-1). Rarely, >100 lesions have been recorded. The lesions typically begin as a small papule at the site of the sandfly bite, which enlarges to 1-3 cm in diameter and may ulcerate over the course of several weeks to months. The shallow ulcer is usually nontender and surrounded by a sharp, indurated, erythematous margin. There is no drainage unless a bacterial superinfection develops. Lesions caused by L. major and L. mexicana usually heal spontaneously after 3-6 mo, leaving a depressed scar. Lesions on the ear pinna caused by L. mexicana, called chiclero ulcer because they were common in chicle harvesters in Mexico and Central America, often follow a chronic, destructive course. In general, lesions caused by L. (Viannia) species tend to be larger and more chronic. Regional lymphadenopathy and palpable subcutaneous nodules or lymphatic cords, the so-called sporotrichoid appearance, are also more common when the patient is infected with organisms of the Viannia subgenus. If lesions do not become secondarily infected, there are usually no complications aside from the residual cutaneous scar.

image

Figure 277-1 Cutaneous and mucosal disease. A, Old World infection (Leishmania major) acquired in Iraq; note 5 papular and nodular lesions on neck. B, New World infection (Leishmania panamensis) in Colombia; purely ulcerative lesion is characteristic of New World disease. C, Healed infection in patient shown in B 70 days after 20 days of meglumine antimoniate treatment; note paper-thin scar tissue over flat re-epithelialized skin.

(A, Courtesy of P. Weina. B, Courtesy of J. Soto. A-C, Modified from Murray HW, Berman JD, Davies CR, et al: Advances in leishmaniasis, Lancet 366:1561–1577, 2005.)

Diffuse Cutaneous Leishmaniasis

DCL is a rare form of leishmaniasis caused by organisms of the L. mexicana complex in the New World, and L. aethiopica in the Old World. DCL manifests as large nonulcerating macules, papules, nodules, or plaques that often involve large areas of skin and may resemble lepromatous leprosy. The face and extremities are most commonly involved. Dissemination from the initial lesion usually takes place over several years. It is thought that an immunologic defect underlies this severe form of cutaneous leishmaniasis.

Mucosal Leishmaniasis

ML (espundia) is an uncommon but serious manifestation of leishmanial infection resulting from hematogenous metastases to the nasal or oropharyngeal mucosa from a cutaneous infection. It is usually caused by parasites in the L. (Viannia) complex. Approximately half of the patients with mucosal lesions have had active cutaneous lesions within the preceding 2 yr, but ML may not develop until many years after resolution of the primary lesion. ML occurs in <5% of individuals who have, or have had, LCL caused by L. (V.) braziliensis. Patients with ML most commonly have nasal mucosal involvement and present with nasal congestion, discharge, and recurrent epistaxis. Oropharyngeal and laryngeal involvement is less common but associated with severe morbidity. Marked soft tissue, cartilage, and even bone destruction occurs late in the course of disease and may lead to visible deformity of the nose or mouth, nasal septal perforation, and tracheal narrowing with airway obstruction.

Visceral Leishmaniasis

VL (kala-azar) typically affects children <5 yr of age in the New World and Mediterranean region (L. infantum/chagasi) and older children and young adults in Africa and Asia (L. donovani). After inoculation of the organism into the skin by the sandfly, the child may have a completely asymptomatic infection or an oligosymptomatic illness that either resolves spontaneously or evolves into active kala-azar. Children with asymptomatic infection are transiently seropositive but show no clinical evidence of disease. Children who are oligosymptomatic have mild constitutional symptoms (malaise, intermittent diarrhea, poor activity tolerance) and intermittent fever; most will have a mildly enlarged liver. In most of these children the illness will resolve without therapy, but in approximately 25% it will evolve to active kala-azar within 2-8 mo. Extreme incubation periods of several years have rarely been described. During the 1st few weeks to months of disease evolution the fever is intermittent, there is weakness and loss of energy, and the spleen begins to enlarge. The classic clinical features of high fever, marked splenomegaly, hepatomegaly, and severe cachexia typically develop approximately 6 mo after the onset of the illness, but a rapid clinical course over 1 mo has been noted in up to 20% of patients in some series (Fig. 277-2). At the terminal stages of kala-azar the hepatosplenomegaly is massive, there is gross wasting, the pancytopenia is profound, and jaundice, edema, and ascites may be present. Anemia may be severe enough to precipitate heart failure. Bleeding episodes, especially epistaxis, are frequent. The late stage of the illness is often complicated by secondary bacterial infections, which frequently are a cause of death. A younger age at the time of infection and underlying malnutrition may be risk factors for the development and more rapid evolution of active VL. Death occurs in >90% of patients without specific antileishmanial treatment.

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Figure 277-2 Visceral leishmaniasis (Leishmania donovani) in Bihar State, India. A, Hepatosplenomegaly and wasting in a young man. B, Children with burn marks over enlarged spleen or liver—local shaman’s unsuccessful remedy.

(A, Courtesy of D. Sacks. B, Courtesy of R. Kenney. A-B, Modified from Murray HW, Berman JD, Davies CR, et al: Advances in leishmaniasis, Lancet 366:1561–1577, 2005.)

VL is an opportunistic infection associated with HIV infection. Most cases have occurred in southern Europe and Brazil, often as a result of needle sharing associated with illicit drug use, with the potential for many more cases as the endemic regions for HIV and VL converge. Leishmaniasis may also result from reactivation of a long-standing subclinical infection. Frequently there is an atypical clinical presentation of VL in HIV-infected individuals with prominent involvement of the gastrointestinal tract and absence of the typical hepatosplenomegaly.

A small percentage of patients previously treated for VL develop diffuse skin lesions, a condition known as post–kala-azar dermal leishmaniasis (PKDL). These lesions may appear during or shortly after therapy (Africa) or up to several years later (India). The lesions of PKDL are hypopigmented, erythematous, or nodular and commonly involve the face and torso. They may persist for several months or for many years.

Laboratory Findings

Patients with cutaneous or mucosal leishmaniasis generally do not have abnormal laboratory results unless the lesions are secondarily infected with bacteria. Laboratory findings associated with classic kala-azar include anemia (hemoglobin 5-8 mg/dL), thrombocytopenia, leukopenia (2,000-3,000 cells/µL), elevated hepatic transaminase levels, and hyperglobulinemia (>5 g/dL) that is mostly immunoglobulin G (IgG).

Differential Diagnosis

Diseases that should be considered in the differential diagnosis of LCL include sporotrichosis, blastomycosis, chromomycosis, lobomycosis, cutaneous tuberculosis, atypical mycobacterial infection, leprosy, ecthyma, syphilis, yaws, and neoplasms. Infections such as syphilis, tertiary yaws, histoplasmosis, paracoccidioidomycosis, as well as sarcoidosis, Wegener granulomatosis, midline granuloma, and carcinoma may have clinical features similar to those of ML. VL should be strongly suspected in the patient with prolonged fever, weakness, cachexia, marked splenomegaly, hepatomegaly, cytopenias, and hypergammaglobulinemia who has had potential exposure in an endemic area. The clinical picture may also be consistent with that of malaria, typhoid fever, miliary tuberculosis, schistosomiasis, brucellosis, amebic liver abscess, infectious mononucleosis, lymphoma, and leukemia.

Diagnosis

The development of one or several slowly progressive, nontender, nodular, or ulcerative lesions in a patient who had potential exposure in an endemic area should raise suspicion of LCL.

Serologic tests for diagnosis of ML or LCL generally have low sensitivity and specificity and offer little for diagnosis. Serologic testing by enzyme immunoassay, indirect fluorescence assay, or direct agglutination is very useful in VL because of the very high level of antileishmanial antibodies. An enzyme-linked immunosorbent assay using a recombinant antigen (K39) has a sensitivity and specificity for VL that is close to 100%. A negative serologic test result in an immunocompetent individual is strong evidence against a diagnosis of VL. Serodiagnostic tests have positive findings in only about half of the patients who are co-infected with HIV.

Definitive diagnosis of leishmaniasis is established by the demonstration of amastigotes in tissue specimens or isolation of the organism by culture. Amastigotes can be identified in Giemsa-stained tissue sections, aspirates, or impression smears in about half of the cases of LCL but only rarely in the lesions of ML. Culture of a tissue biopsy or aspirate, best performed by using Novy-McNeal-Nicolle (NNN) biphasic blood agar medium, yields a positive finding in only about 65% of cases of CL. Identification of parasites in impression smears, histopathologic sections, or culture medium is more readily accomplished in DCL than in LCL. In patients with VL, smears or cultures of material from splenic, bone marrow, or lymph node aspirations are usually diagnostic. In experienced hands, splenic aspiration has a higher diagnostic sensitivity, but it is rarely performed in the USA because of the risk for bleeding complications. A positive culture result allows speciation of the parasite, usually by isoenzyme analysis by a reference laboratory, which may have therapeutic and prognostic significance.

Treatment

Specific antileishmanial therapy is not routinely indicated for uncomplicated LCL caused by strains that have a high rate of spontaneous resolution and self-healing (L. major, L. mexicana). Lesions that are extensive, severely inflamed, or located where a scar would result in disability (near a joint) or cosmetic disfigurement (face or ear), that involve the lymphatics, or that do not begin healing within 3-4 mo should be treated. Cutaneous lesions suspected or known to be caused by members of the Viannia subgenus (New World) should be treated because of the low rate of spontaneous healing and the potential risk for development of mucosal disease. Similarly, patients with lesions caused by L. tropica (Old World), which are typically chronic and nonhealing, should be treated. All patients with VL or ML should receive therapy.

The pentavalent antimony compounds (sodium stibogluconate [Pentostam, GlaxoSmithKline, Uxbridge, UK] and meglumine antimoniate [Glucantime, Aventis, Strasbourg, France]) have been the mainstay of antileishmanial chemotherapy for >40 yr. These drugs have similar efficacies, toxicities, and treatment regimens. Currently, for sodium stibogluconate (available in the USA from the Centers for Disease Control and Prevention, Atlanta, Georgia), the recommended regimen is 20 mg/kg/day intravenously or intramuscularly for 20 days (for LCL and DCL) or 28 days (for ML and VL). Repeated courses of therapy may be necessary in patients with severe cutaneous lesions, ML, or VL. An initial clinical response to therapy usually occurs in the 1st wk of therapy, but complete clinical healing (re-epithelialization and scarring for LCL and ML, and regression of splenomegaly and normalization of cytopenias for VL) is usually not evident for weeks to a few months after completion of therapy. Cure rates with this regimen of 90-100% for LCL, 50-70% for ML, and 80-100% for VL were common in the 1990s, but clinical resistance to antimony therapy has become common in parts of India, East Africa, and Latin America. Furthermore, a very low cure rate in children <5 yr of age has been reported in Colombia. Relapses are common in patients who do not have an effective antileishmanial cellular immune response, such as those who have DCL or are co-infected with HIV. These patients often require multiple courses of therapy or a chronic suppressive regimen. When clinical relapses occur, they are usually evident within 2 mo after completion of therapy. Adverse effects of antimony therapy are dose and duration dependent and commonly include fatigue, arthralgias and myalgias (50%), abdominal discomfort (30%), elevated hepatic transaminase level (30-80%), elevated amylase and lipase levels (almost 100%), mild hematologic changes (slightly decreased leukocyte count, hemoglobin level, and platelet count) (10-30%), and nonspecific T-wave changes on electrocardiography (30%). Sudden death due to cardiac toxicity is extremely rare and is usually associated with use of very high doses of pentavalent antimony.

Amphotericin B desoxycholate and the amphotericin lipid formulations are very useful in the treatment of VL or ML and in some regions have replaced antimony as first-line therapy. Amphotericin B desoxycholate at doses of 0.5-1.0 mg/kg every day or every other day for 14-20 doses achieved a cure rate for VL of close to 100%, but the renal toxicity commonly associated with amphotericin B was common. The lipid formulations of amphotericin B are especially attractive for treatment of leishmaniasis because the drugs are concentrated in the reticuloendothelial system and are less nephrotoxic. Liposomal amphotericin B is highly effective, with a 90-100% cure rate for VL in immunocompetent children, some of whom were refractory to antimony therapy. Liposomal amphotericin B (Ambisome, Gilead Sciences, Foster City, CA) is approved by the U.S. Food and Drug Administration for treatment of VL at a recommended dose for immunocompetent patients of 3 mg/kg on days 1-5, 14, and 21 and should be considered for first-line therapy in the USA. Therapy for immunocompromised patients may need to be prolonged. Parenteral treatment of VL with the aminoglycoside paromomycin (aminosidine) has efficacy (∼95%) similar to that of amphotericin B in India. Recombinant human interferon-γ has been successfully used as an adjunct to antimony therapy in the treatment of refractory cases of ML and VL. It is not effective alone and has the frequent side effects of fever and flulike symptoms. Miltefosine, a membrane-activating alkylphospholipid, has been recently developed as the 1st oral treatment for VL and has a cure rate of 95% in Indian patients with VL when administered orally at 50-100 mg/day for 28 days. Gastrointestinal adverse effects were frequent but did not require discontinuation of the drug. Treatment of LCL with oral drugs has had only modest success. Ketoconazole has been effective in treating adults with LCL caused by L. major, L. mexicana, and L. panamensis but not L. tropica or L. braziliensis. Fluconazole 200 mg orally once daily for 6 wk was demonstrated in adults to modestly increase the rate of healing of CL caused by L. major in Saudi Arabia. Miltefosine 2.5 mg/kg/day orally for 20 days had a 91% efficacy in treating CL in Colombia (L. panamensis) but was significantly less effective in patients from Guatemala (L. braziliensis). Topical treatment of CL with paromomycin plus methylbenzethonium chloride ointment has been effective in selected areas in the both Old and New World. Enhanced drug development efforts and clinical trials of new drugs are clearly needed, especially in children.

Prevention

Personal protective measures should include avoidance of exposure to the nocturnal sandflies and, when necessary, the use of insect repellent and permethrin-impregnated mosquito netting. Where peridomiciliary transmission is present, community-based residual insecticide spraying has had some success in reducing the prevalence of leishmaniasis, but long-term effects are difficult to maintain. Control or elimination of infected reservoir hosts (e.g., seropositive domestic dogs) has had limited success. Where anthroponotic transmission is thought to occur, early recognition and treatment of cases are essential. Several vaccines have been demonstrated to have efficacy in experimental models, and vaccination of humans or domestic dogs may have a role in the control of the leishmaniases in the future.

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