VL (also known as kala-azar, a Hindi term meaning “black fever”) is caused by the Leishmania donovani complex, which includes L. donovani and Leishmania infantum (the latter designated Leishmania chagasi in the New World); these species are responsible for anthroponotic and zoonotic transmission, respectively. India and neighboring Bangladesh, Sudan and neighboring South Sudan, Ethiopia, and Brazil are the four largest foci of VL and account for 90% of the world’s VL burden. 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, South Sudan, Ethiopia, Kenya, Uganda, and Somalia report VL. In Sudan and South 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 infection. In Mediterranean Europe, 70% of adult VL cases are associated with HIV co-infection. The combination is deadly because of the combined impact of the two infections 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. After the introduction of highly active antiretroviral therapy, the incidence of HIV–VL co-infection declined significantly in Europe; however, ~30 and 5% of VL patients are co-infected with HIV in Ethiopia and India, respectively.
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. A direct role for IL-10 in the pathology of VL in humans is supported by studies demonstrating that IL-10 blockade can enhance IFN-γ responses in whole blood from VL patients. 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, 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 as well as 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. 221-3). 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. 221-1). 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 min. Except in East Africa (where both its sensitivity and its specificity are lower), the sensitivity of the rK39 rapid diagnostic test (RDT) in immunocompetent individuals is ~98% and its specificity is ~90%. In Sudan, an RDT based on a new synthetic polyprotein, rK28, was more sensitive (96.8%) and specific (96.2%) than rK39-based RDTs. Since these antibody detection tests remain positive for years after cure, they cannot be used for measurement of cure or detection of relapse. Qualitative detection of leishmanial nucleic acid by polymerase chain reaction (PCR) or by loop-mediated isothermal amplification (LAMP) and quantitative detection by real-time PCR are highly sensitive; however, because the capacity to perform these tests is confined to specialized laboratories, they 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 GENERAL CONSIDERATIONS
Severe anemia should be corrected by blood transfusion, and other comorbid conditions should be managed promptly. Treatment of VL is complex because the optimal drug, dosage, and duration vary with the endemic region. Despite 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 liposomal—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 (LAmB) 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 antimoniate (85 mg of SbV/mL). The daily dose is 20 mg/kg by 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. AMPHOTERICIN B
AmB is currently used as a first-line drug in Bihar, India. In other 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.
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. LAmB has been used extensively to treat VL in all parts of the world. With a terminal half-life of ~150 h, LAmB 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, ≥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. This single-dose regimen is the preferred treatment in India, Bangladesh, and Nepal. Adverse effects of LAmB are usually mild and include infusion reactions, backache, and occasional reversible nephrotoxicity. PAROMOMYCIN
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 94.6%. 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. Paromomycin, in combination with Sbv, is used in sub-Saharan Africa. MILTEFOSINE
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 have resulted in a cure rate of 94% in India. However, recent studies from the Indian subcontinent indicate a decline in the cure rate. 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
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. In a study from India, one dose of LAmB (5 mg/kg) followed by miltefosine for 7 days, paromomycin for 10 days, or both miltefosine and paromomycin simultaneously for 10 days (in their usual daily doses) produced a cure rate of >97% (all three combinations). In Africa, a combination of SbV and paromomycin given for 17 days was as effective and safe as SbV given for 30 days.
Prognosis of Treated Vl Patients
Recovery from VL is quick. Within a week after the start of treatment, defervescence, regression of splenomegaly, weight gain, and recovery of hematologic parameters are evident. With effective treatment, no parasites are recovered from tissue aspirates at the post-treatment 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. Where both infections are endemic, VL behaves as an opportunistic infection in HIV-1-infected patients. HIV infection can increase the risk of VL development by several-fold 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—e.g., infiltration of the skin, oral mucosa, gastrointestinal tract, lungs, and other organs. Serodiagnostic tests may be negative in up to 50% of patients. Parasites can be recovered from unusual sites such as bronchoalveolar lavage fluid and buffy coat. LAmB 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 experience a relapse within 1 year. Pentavalent antimonials and AmB deoxycholate can also be used where LAmB 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. Because 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 of the management of HIV/VL co-infection. Secondary prophylaxis with pentamidine or lipid 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 221-2, and disease in an Indian patient is depicted in Fig. 221-4.
TABLE 221-2Clinical, Epidemiologic, and Therapeutic Features of Post–Kala-Azar Dermal Leishmaniasis: East Africa and the Indian Subcontinent ||Download (.pdf) TABLE 221-2 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 and South Sudan ||Bangladesh |
|Incidence among patients with VL ||~50% ||~2–17% |
|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 in minority of patients |
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 was treated with prolonged courses (up to 120 days) of pentavalent antimonials. This prolonged course frequently led to noncompliance. The alternative—several courses of AmB spread over several months—is expensive and unacceptable for most patients. Oral miltefosine for 12 weeks, in the usual daily doses, cures most patients with Indian PKDL. The efficacy of LAmB is being tested on the Indian subcontinent. 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.