128 - 233 Leishmaniasis

233 Leishmaniasis

GLOBAL CONSIDERATIONS In Europe, B. divergens infection is considered a medical emer­ gency. The recommended approach is immediate, complete RCE combined with administration of clindamycin plus oral quinine (Table 232-1). Some cases have been cured with RCE and clindamy­ cin monotherapy. Anemia may persist for >1 month and require blood transfusion. A severe case of B. divergens infection resolved during therapy with atovaquone plus azithromycin. A relapse in a spleen-intact individual was treated with atovaquone-proguanil plus azithromycin. The first-line therapy for B. venatorum infec­ tion in Europe has been IV or oral clindamycin plus quinine. In a patient intolerant to quinine, infection was cured after administra­ tion of atovaquone plus azithromycin. A pediatric case of mild

B. venatorum infection in China was successfully treated by a stan­ dard course of atovaquone plus azithromycin. ■ ■PREVENTION Given the lack of vaccine and chemoprophylaxis, individuals who reside in endemic areas, especially those at risk of severe babesiosis, should wear protective clothing, apply tick repellents to the skin and permethrin to clothing, and limit outdoor activities where ticks abound from May through October. The skin should be thoroughly examined after outdoor activities and ticks carefully removed with tweezers. As babesiosis continues to expand into new areas and because climate change has begun to reshape this expansion, physicians should be increasingly aware of this once neglected disease. ■ ■FURTHER READING Krause PJ et al: Clinical practice guidelines by the Infectious Diseases Society of America (IDSA): 2020 guideline on diagnosis and manage­ ment of babesiosis. Clin Infect Dis 72:185, 2021. Rogers R et al: Broad antimicrobial resistance in a case of relapsing babesiosis successfully treated with tafenoquine. Clin Infect Dis 76:741, 2023. Swanson M et al: Trends in reported babesiosis cases — United States, 2011–2019. MMWR Morb Mortal Wkly Rep 72:273, 2023. Tannous T et al: Red cell exchange as adjunctive therapy for babesio­ sis: Is it really effective? Transfus Med Rev 35:16, 2021. Tonnetti L et al: Babesia blood testing: The first-year experience. Transfusion 62:135, 2022. Shyam Sundar

Leishmaniasis 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 rang­ ing 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). ■ ■ETIOLOGY AND LIFE CYCLE Leishmaniasis is caused by ~20 species of the genus Leishmania in the order Kinetoplastida and the family Trypanosomatidae (Table 233-1). Several clinically important species are of the subspecies Viannia. The organisms are transmitted by phlebotomine sandflies of the genus Phle­ botomus 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.

Leishmania organisms occur in two forms: extracellular, flagellate promastigotes (length, 10–20 μm) in the sandfly vector and intracellu­ lar, nonflagellate amastigotes (length, 2–4 μm; Fig. 233-1 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, sand­ flies pick up amastigotes, which transform into the flagellate form in the flies’ posterior midgut and multiply by binary fission; the promas­ tigotes then migrate to the anterior midgut and can infect a new host when flies take another blood meal. ■ ■EPIDEMIOLOGY Leishmaniasis occurs in 99 countries—most of them developing—in tropical and temperate regions (Fig. 233-2). More than 1 billion people live in areas endemic for leishmaniasis and are at risk of infection. An estimated 30,000 new cases of VL and more than 1 million new cases of CL occur annually. CL is common in South America, Africa, and Asia, whereas VL commonly occurs in East Africa, Brazil, and the Indian subcontinent. ML is limited to South America. The distribution of Leishmania is limited by the distribution of sandfly vectors. CHAPTER 233 ■ ■VISCERAL LEISHMANIASIS 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; these species are responsible for anthroponotic and zoonotic transmission, respectively. East Africa now has the highest incidence of VL, followed by Brazil and the Indian subcontinent. In the Indian subcontinent (India, Nepal, and Bangladesh), where a VL elimination program has been implemented, VL incidence has markedly declined. In these three countries, the World Health Organization (WHO) recently announced the elimina­ tion of VL as a public health problem in Bangladesh and a steep decline in the incidence in Nepal, and India reported a 98.7% decline. 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. Leishmaniasis 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. Immunopathogenesis  The majority of individuals infected by L. donovani or L. infantum mount a successful immune response and control the infection, never developing symptomatic disease. Fortyeight hours after intradermal injection of killed promastigotes, these individuals exhibit delayed-type hypersensitivity (DTH) to leishman­ ial antigens in the leishmanin skin test (also called the Montenegro

TABLE 233-1  Geographic Distribution and Characteristic Epidemiology of Leishmaniases CLINICAL SYNDROME SPECIES VECTOR RESERVOIR TRANSMISSION SETTING ORGANISM, ENDEMIC REGION Leishmania donovani Complex South Asia VL, PKDL L. donovani Phlebotomus argentipes Sudan, South Sudan, Somalia, Ethiopia, Kenya, Uganda VL, PKDL L. donovani P. orientalis,

P. martini Mediterranean basin, Middle East, Central Asia, China VL, CL L. infantum P. perniciosus,

P. ariasi Middle East, Saudi Arabia, Yemen VL L. donovani P. perniciosus,

P. ariasi Central and South America VL, CL L. infantuma Lutzomyia longipalpis Azerbaijan, Armenia, Georgia, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, Uzbekistan VL L. infantum P. turanicus Humans, dogs, foxes Anthroponotic, zoonotic L. tropica Western India to Turkey, parts of North and East Africa CL, leishmaniasis recidivans L. tropica P. sergenti Humans Anthroponotic Urban domestic, peridomestic L. major Western and Central Asia, North and sub-Saharan Africa CL L. major P. papatasi,

P. duboscqi Kazakhstan, Turkmenistan, Uzbekistan CL L. major P. papatasi,

P. duboscqi L. aethiopica PART 5 Infectious Diseases Ethiopia, Uganda, Kenya CL, DCL L. aethiopica P. longipes,

P. pedifer Subspecies Viannia Peru, Ecuador CL, ML L. (V.) peruviana Lutzomyia verrucarum,

L. peruensis Guyana, Surinam, French Guyana, Ecuador, Brazil, Colombia, Bolivia CL, ML L. (V.) guyanensis L. umbratilis Sloths, arboreal anteaters, opossums 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 L. mexicana Complex Central America and northern parts of South America CL, ML, DCL L. amazonensis L. flaviscutellata Forest rodents Zoonotic Tropical forest and deforested areas   CL, ML, DCL L. mexicana L. olmeca Variety of forest rodents and marsupials   CL, DCL L. pifanoi L. olmeca Variety of forest rodents and marsupials aL. infantum is designated L. chagasi in the New World. Abbreviations: CL, cutaneous leishmaniasis; DCL, diffuse cutaneous leishmaniasis; ML, mucosal leishmaniasis; PKDL, post–kala-azar dermal leishmaniasis; VL, visceral leishmaniasis. skin test). Results in mouse models indicate that the development of acquired resistance to leishmanial infection is controlled by the pro­ duction of interleukin (IL) 12 by antigen-presenting cells and the sub­ sequent 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 proinflam­ matory 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

Humans Anthroponotic Rural, domestic Humans, rodents in Sudan, canines Anthroponotic, occasionally zoonotic Majority peridomestic, occasionally sylvatic Dogs, foxes, jackals Zoonotic Domestic, peridomestic Dogs, foxes, jackals Zoonotic Domestic, peridomestic Foxes, dogs, opossums Zoonotic Domestic, peridomestic, periurban Domestic Nile rats, rodents Zoonotic Sylvatic, peridomestic Gerbils Zoonotic Rural Hyraxes Zoonotic Sylvatic, peridomestic Wild rodents Zoonotic Andean Valleys Zoonotic Tropical forest Forest rodents, peridomestic animals Zoonotic Tropical forest and deforested areas Zoonotic Tropical forest and deforested areas Zoonotic Tropical forest and deforested areas IL-10 blockade can enhance antigen-specific IFN-γ responses in whole blood from VL patients and IL-10 neutralization promotes parasitic killing. 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 activa­ tion 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

FIGURE 233-1  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. 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. Clinical Features  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 incubation period is 2–3 months but may be up to 1 year or more. 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. 233-3). Hepatomegaly (usually moderate) soon follows. Visceral leishmaniasis Cutaneous leishmaniasis Visceral and cutaneous leishmaniasis Low endemic region Non endemic region FIGURE 233-2  Worldwide distribution of human leishmaniasis.

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 hemor­ rhages, and gastrointestinal bleeding are associated with thrombocyto­ penia. Secondary infections such as 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.

Leukopenia and anemia occur early and are followed by throm­ bocytopenia. There is a marked polyclonal increase in serum immu­ noglobulins. Serum levels of hepatic aminotransferases are raised in a significant proportion of patients, and serum bilirubin levels are elevated occasionally. Renal dysfunction is uncommon. Laboratory Diagnosis  Demonstration of amastigotes in smears of tissue aspirates remains the gold standard for the diagnosis of VL (Fig. 233-1). 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. To circumvent these invasive procedures, 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. CHAPTER 233 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 specificity are lower), the sensitivity of the rK39 rapid diagnostic test (RDT) in immunocompetent individuals is ~98% and its specificity is ~90%. RDTs— based on a new synthetic polyprotein, rK28—performed better in Sudan, but are not available commercially. 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) and quantitative detection by Leishmaniasis

PART 5 Infectious Diseases FIGURE 233-3  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. real-time PCR are highly sensitive and have the added advantage of species identification. However, because the capacity to perform these tests is confined to specialized laboratories, they are yet to be used for routine diagnosis of VL in endemic areas. Using blood samples, loopmediated isothermal amplification (LAMP) of nucleic acids performs better compared with microscopy. A simple visual readout with minimum laboratory equipment requirements makes it attractive for pointof-care diagnostics for VL and post–kala-azar dermal leishmaniasis (PKDL), and it is likely to be used increasingly in the future. Differential Diagnosis  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 6−12 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 Drug Service (telephone: 404-639-3670; email: drugservice@cdc.gov). 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 (and its liposomal formulations) is currently used as a firstline drug in the Indian Subcontinent. Because of a better safety profile, LAmB is now the preferred drug of choice in other parts of the world, as well. 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. In addition to oral miltefosine (see below), 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 used in the elimination program in the Indian subcontinent. 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 is 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 combina­ tion with SbV, is used in sub-Saharan Africa. MILTEFOSINE Miltefosine, an alkylphosphocholine, is the first oral compound approved for the treatment of leishmaniasis in several endemic countries including the United States. This drug has a long half-life (150–200 h); its mechanism of action is not clearly understood. The recommended therapeutic regimens consist of 28 consecutive days of treatment in doses of 50 mg for patients weighing <25 kg, a twicedaily dose of 50 mg for patients weighing ≥25 kg, and 2.5 mg/kg

for children 2–11 years of age. In children, allometric dosing has been suggested for adequate exposure to the drug. These regimens have resulted in a cure rate of ~94% in India. However, recent stud­ ies 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 subside spontaneously after a few days. Rare instances 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 after meals to minimize the gastrointestinal adverse events, and to ensure completion of treatment and to minimize the risk of resis­ tance induction. Because miltefosine is teratogenic in rats, its use is contraindicated during pregnancy and (unless contraceptive mea­ sures are strictly adhered to for at least 5 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 compli­ ance 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, or 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 and is the preferred first-line treatment of VL. Recently, in a phase 3 trial from East Africa, this prevailing 17-day regimen was compared with combinations of paromomycin and miltefosine for 14 days as doses described above. The cure rates were similar, and this new combination has been proposed as an alternative to the standard 17-day regimen. 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 param­ eters are evident. With effective treatment, no parasites are recovered from tissue aspirates at the posttreatment evaluation. Continued clinical improvement over 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 retreatment with AmB or its lipid formulations. VL in the Immunocompromised Host  HIV/VL co-infection has been reported from 45 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 bron­ choalveolar 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 for the Americas and Mediterranean countries and is approved by the FDA, but most patients experience a relapse within 1 year. Recently, there has been a significant change in the WHO recommendations for treatment of HIV–VL co-infection in the Indian subcontinent and East Africa. LAmB infusions (total dose 30 mg/kg; 5 mg/kg on days 1, 3, 5, 7, 9, and 11) co-administered with oral miltefosine (100 mg/d for 14 days for the Indian subcontinent and 28 days for East Africa) should now be used to treat HIV–VL co-infection. 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 coinfection 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 fre­ quency 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.

CHAPTER 233 Post–Kala-Azar Dermal Leishmaniasis  On the Indian sub­ continent 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 PKDL in these two regions are listed in Table 233-2, and disease in an Indian patient is depicted in Fig. 233-4. Leishmaniasis In PKDL, parasites are scanty in hypopigmented macules but may be seen and cultured more easily from nodular lesions. Cellular infil­ trates 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, clin­ ical findings supported by demonstration of parasites in the slit skin smears, or by demonstrating parasitic DNA in PCR. Sensitivity of skin smears is quite low, and positive serology does not help as it remains positive for several years after the cure of VL. Indian PKDL was treated with prolonged courses (up to 120 days) of pentavalent antimonials. This prolonged course was toxic and frequently led to noncompliance. TABLE 233-2  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% 5–15% 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 Sodium stibogluconate for 2–3 months Miltefosine for 12 weeks Natural course Spontaneous cure in majority of patients Spontaneous cure rarely Abbreviations: PKDL, post–kala-azar dermal leishmaniasis; VL, visceral leishmaniasis.

PART 5 Infectious Diseases FIGURE 233-4  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. The alternative—three to four 20-day courses of AmB spread over several months—is expensive and unacceptable for most patients. Except for cosmetic reasons, these patients do not have any physical limitation, and thus motivation for such long and arduous treatment is very low. This leads to either no or incomplete treatment. In the Indian subcontinent, the currently recommended regimen is oral miltefosine for 12 weeks, in the usual daily doses. Though initially cure rates were high, a decline in its efficacy is now being reported in some studies. Furthermore, there are reports of ocular toxicity with this regimen in 3.7% of patients. The efficacy of either LAmB alone (20 mg/kg)

or in combination with miltefosine (for 3 weeks) in PKDL has been recently tested in the Indian subcontinent; the efficacy was greater than 80% with both regimens. In East Africa, a majority of patients experi­ ence spontaneous healing. In those with persistent lesions, the response to 60 days of treatment with a pentavalent antimonial is good. ■ ■CUTANEOUS LEISHMANIASIS CL can be broadly divided into Old World and New World forms. Old World CL caused by Leishmania tropica is anthroponotic and is con­ fined to urban or suburban areas throughout its range. Zoonotic CL is most commonly due to Leishmania major, which naturally parasitizes several species of desert rodents that act as reservoirs over wide areas of the Middle East, Africa, and central Asia. Local outbreaks of human disease are common. Major outbreaks currently affect Afghanistan, Syria, Iraq, Lebanon, and Turkey in association with refugees and population movement. CL is increasingly seen in tourists and military personnel on mission in CL-endemic regions of countries and as a coinfection in HIV-infected patients. Leishmania 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 Leishmania mexicana, Leishmania (Viannia) panamensis, and Leishmania 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, Leishmania (Viannia) braziliensis has adapted to peridomestic and urban animals, and CL due to this organism is increasingly becoming an urban dis­ ease. In the United States, a few cases of CL have been acquired indig­ enously in Texas. Immunopathogenesis  As in VL, the proinflammatory (TH1) response in CL may result in either asymptomatic or subclinical infec­ tion. However, in some individuals, the immune response causes ulcer­ ative skin lesions, the majority of which heal spontaneously, leaving a scar. Healing is usually followed by immunity to reinfection with that species of parasite. Clinical Features  A few days or weeks after the bite of a sandfly, a papule develops and grows into a nodule that ulcerates over weeks or months. The base of the ulcer, which is usually painless, consists of necrotic tissue and crusted serum, but secondary bacterial infection sometime 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. 233-5). 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, whereas 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 Leishmania (Viannia) peruviana closely resemble those seen in the Old World; however, lesions on the pinna of the ear are com­ mon, 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. Differential Diagnosis  A typical history (an insect bite followed by the events leading to ulceration) in a resident of or a returning traveler from an endemic zone, strongly suggests CL. Cutaneous tuber­ culosis, fungal infections, leprosy, sarcoidosis, and malignant ulcers are sometime mistaken for CL. Laboratory Diagnosis  Demonstration of amastigotes in material obtained from a lesion remains the diagnostic gold standard. Micro­ scopic 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 or LAMP is more sensitive than FIGURE 233-5  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, Retired Medical Officer, World Health Organization, Geneva, Switzerland.)

microscopy and culture and allows identification of Leishmania to the species level. Quantitative PCR may be used to monitor treatment responses. This information is important in decisions about therapy because responses to treatment can vary with the species. 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. The exceptions to this rule are CL caused by Leishmania (Viannia) 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. aethi­ opica, which responds to paromomycin (16 mg/kg daily) but not to antimonials. Relapses usually respond to a second course of treat­ ment. In Peru, topical imiquimod (5–7.5%) plus parenteral antimo­ nials 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 flu­ conazole (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. Keto­ conazole (600 mg/d for 28 days) is 76–90% effective in CL due to

L. (V.) panamensis and L. mexicana in Panama and Guatemala. Orally administered miltefosine makes it very attractive and is a major advancement in the treatment of CL. Miltefosine has been used in CL in doses of 2.5 mg/kg for 28 days. This agent is effective against L. major infections. Recent Pan American Health Organiza­ tion guidelines recommend intralesional pentavalent antimonials in patients with localized CL caused by L. braziliensis and L. ama­ zonensis. There is a strong recommendation for oral miltefosine treatment for New World CL where L. panamensis, L. mexicana, L. guyanensis, and L. braziliensis are the species involved. Overall, there has been a tilt toward the use of miltefosine in CL and ML instead of antimonials, both in the New and Old Worlds. In Brazil, miltefosine cured 71% of patients with L. (V.) guyanensis infection. 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, either alone or with 0.5% gentamicin or 12% methylbenzonium chloride, cured 70–82% 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 radio­ frequency 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 does not develop, 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 con­ fined to the face or a limb but spread over months or years to other areas of the skin. They may be symmetrically or asymmetrically dis­ tributed and include papules, nodules, plaques, and areas of diffuse infiltration. These lesions do not ulcerate. The overlying skin is usu­ ally 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.

■ ■MUCOSAL LEISHMANIASIS The subgenus Viannia is widespread from the Amazon basin to Paraguay and Costa Rica and is responsible for deep sores and for ML (Table 233-1). 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 typically caused by L. (V.) bra­ ziliensis 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 (L. chagasi), or L. donovani. CHAPTER 233 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. 233-6) 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 involve­ ment of the pharynx and larynx leads to difficulty in swallowing and phonation. The lips, cheeks, and soft palate may also be affected. Sec­ ondary 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. Leishmaniasis Laboratory Diagnosis  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 admin­ istered 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 unre­ sponsive, presumably because of resistance in the parasite. In this situation, AmB should be used. An AmB deoxycholate dose total­ ing 25–45 mg/kg is appropriate. There are no controlled trials of LAmB, 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 is the prognosis; thus, prompt, effective treatment and regular follow-up are essential.