How I Approach Leishmaniasis: Diagnosis and Treatment in the United States

Abstract

Leishmaniasis is a vector-borne disease caused by over 20 species of obligate intracellular protozoa belonging to the genus Leishmania. Leishmaniasis has a global distribution, including in the United States, and can cause a spectrum of clinical syndromes, including cutaneous, mucosal, and visceral diseases depending on host factors and the infecting Leishmania spp. Accurate diagnosis, including Leishmania species identification, is an important step to guide the most appropriate therapeutic intervention. Antileishmanial therapy is dependent on the Leishmania spp. identified, the clinical syndrome, and the child’s immune system. However, many treatment regimens for children have been extrapolated from adult clinical trials, which may lead to underdosing and subsequent poor outcomes in infected children. Additional research is urgently needed to help guide therapy for children and determine appropriate antileishmanial agents, doses, and treatment courses for children with leishmaniasis.

INTRODUCTION

Leishmaniasis is a vector-borne disease caused by over 20 species of obligate intracellular protozoa belonging to the genus Leishmania and the subgenera Leishmania, Mundinia, and Viannia and is endemic in over 98 countries worldwide [1]. Leishmaniasis is also considered a neglected tropical disease, disproportionately affecting those living in resource-limited regions of the world [2–4]. Disease prevalence is highly linked to environmental and social disruption such as deforestation, climate change, urbanization, wars, and political conflict [5]. The clinical manifestations of leishmaniasis can have significant life-long effects on children, including significant societal stigmatization secondary to disfiguration that perpetuates the cycle of poverty (Figure 1).

Figure 1.

Summary of leishmaniasis.

Pathogenesis

Transmission occurs when the female phlebotomine sandfly (Family Psychodidae) takes a blood meal and injects Leishmania spp. promastigotes into the host dermis, where the parasites are phagocytized by dermal macrophages and other professional antigen-presenting cells. Leishmania promastigotes transform intracellularly into amastigotes, which subsequently parasitize a variety of host cell types. Infection by Leishmania can lead to a spectrum of clinical syndromes, including visceral (often referred to as kala-azar, Hindi for “black fever”), mucosal, and cutaneous disease [6]. While cutaneous leishmaniasis (CL) is the most common clinical presentation, visceral leishmaniasis (VL) is associated with the highest mortality, especially if left untreated; mucosal leishmaniasis (ML), while not often fatal, is physically destructive and may lead to disfigurement and poor quality of life for those affected.

Epidemiology

There are approximately 4.7 million people in the world with leishmaniasis [7], with 700 000 to 1 million new cases per year [8]. Based on global disease surveillance, the countries with the highest burden of CL (>6000 cases/year) include Afghanistan, Algeria, Brazil, Colombia, Iraq, Pakistan, and the Syrian Arabic Republic. VL most commonly occurs (>1000 cases/year) in Brazil, Ethiopia, Eritrea, Kenya, India, and Sudan [9]. Because the infecting Leishmania spp. typically determines the clinical presentation and these species have distinct geographic distributions, leishmaniasis is often categorized regionally, with infection acquired from the eastern hemisphere (Asia, Africa, Southern Europe) is referred to as “Old World” disease, while infection acquired from the western hemisphere (south-central Texas to Central and South America) is referred to as “New World” disease [10].

In the Americas, over 30% of CL and ML cases occur in individuals younger than 20 years of age and 13% in children less than 10 years of age. More strikingly, approximately 43% of VL cases occur in individuals under 19 years of age, with 35% occurring in children under 10 years of age [11]. In other endemic regions outside of the Americas, pediatric cases are often the majority of Leishmania cases. Following malaria, leishmaniasis is the second-leading cause of death due to a parasitic infection in children under 5 years of age, and the third in children 5–14 years of age, causing an estimated 3338 deaths in children under 15 years of age in 2019, as well as 382 `634 disability-adjusted life years (DALYs) for individuals under 20 (although true numbers may be as high as 10 697 deaths and greater than 1 million DALYs) [12]. Case-fatality rates from VL in children range from 7% to 10% [13, 14], with higher mortality risk identified in children with malnutrition, cell-mediated immunosuppression (HIV), and those affected by social determinants of health such as poverty [15, 16].

While leishmaniasis is uncommon in the United States (US), it is an important clinical entity for healthcare providers to be able to recognize and treat, especially in the returning traveler and military, immigrant, and refugee populations, as well as those living in the Southern US. From 2002 to 2016, the US military reported over 2000 imported cases of leishmaniasis as result of military deployment to Iraq and Afghanistan [17]. Additionally, from 1997 to 2017, 916 cases of leishmaniasis were reported in returning travelers (mainly from Bolivia and Costa Rica) and another 97 in immigrants coming from Syria and Afghanistan [18]. In recent years, the crisis in Afghanistan has led to the resettlement of many Afghan adults and children in the US [12]; because of the high rates of leishmaniasis (particularly cutaneous disease) in Afghanistan, the Centers for Disease Control (CDC) recommends primary care providers maintain a high degree of suspicion for leishmaniasis during initial medical evaluation for recently arrived Afghan individuals [19]. It is also important to note that in the US, the sandfly vector is present in many areas of the south leading to potential local transmission. Furthermore, based on reported cases, Texas and Oklahoma are consider endemic for CL [20, 21]. From 2007 to 2017, a case series described 41 cases of locally acquired CL in the US, including children as young as 3 years of age. Of those who had Leishmania spp. documented, all were caused by Leishmania mexicana [20]. Unfortunately, despite the presence of the sandfly within many parts of the southern US, the known autochthonous cases (locally acquired) within Texas and Oklahoma as well as large resettlement populations from highly endemic regions, leishmaniasis is not a reportable disease in the US outside of Texas. Thus, the true burden of disease in the US remains unknown.

CLINICAL MANIFESTATIONS

Visceral Leishmaniasis

VL is mainly caused by Leishmania donovani (“Old World”) as well as Leishmania infantum/chagasi and Leishmania Mundinia martiniquensis (both “Old World” and “New World”) and has an incubation period that can range from a few weeks to several years (though clinical signs and symptoms typically develop within 2 to 6 months after initial infection). Symptoms are nonspecific, and generally consist of subacute onset of fever, malaise, weight loss, lymphadenopathy, and abdominal discomfort secondary to splenomegaly, with or without hepatomegaly. As disease persists, parasites accumulate in the liver, bone marrow, and spleen, causing cytopenia particularly anemia, cachexia, hypoalbuminemia, and edema. Hemorrhage from body sites such as the nasal mucosa and gingiva can occur secondary to thrombocytopenia [22–24]. Even with treatment, VL has fatality rates as high as 10%, emphasizing the need for prompt recognition and appropriate treatment. Post-kala-azar dermal leishmaniasis is a known sequel of treated VL most commonly seen in India and Sudan as a result of infection due to L. donovani [25, 26].

Cutaneous Leishmaniasis

CL is often regarded as a spectrum of disease, with presentations ranging from localized to more diffuse involvement. Leishmania spp. that cause CL include L.L. major, L.L. tropica, L.L. aethiopica as well as L.L. donovani, L.L. infantum/chagasi (“Old World”), and L.L. mexicana species complex (mexicana, amazonensis, venezuelensis), L.L. infantum/chagasi, and the Viannia subgenus (L.V. guyanensis, L.V. panamensis, L.V. peruviana, and L.V. braziliensis) (“New World”). Localized lesions begin at the site of the sandfly bite as a flesh-colored or erythematous papule/nodule that commonly enlarges to a painless ulcer with a characteristic indurated border (Figure 2), although some lesions may never ulcerate. Lesions can be solitary or multiple, can be associated with subcutaneous nodules or lymphadenopathy, and can resolve spontaneously depending on the Leishmania spp. Lesions are commonly found on areas of exposed skin such as the face/head, arms, and legs. Complications of CL include Leishmaniasis recidivans (new cutaneous lesion which evolves on the periphery of a previously healed skin lesion caused by L.L. tropica) as well as wide-spread nodular and plaque lesions seen in diffuse/disseminated CL (L.L. aethiopica, L.L. mexicana, L.L. amazonensis, and L.V. braziliensis) CL in the setting of cell-mediated immunodeficiency [27].

Figure 2.

Cutaneous leishmaniasis lesion caused by L.V. braziliensis (photo credit: Jill Weatherhead).

Mucosal or Mucocutaneous Leishmaniasis

ML, also known as espundia, is metastatic sequela of “New World” Leishmania Viannia subspecies braziliensis, guyanensis, and panamensis, and more rarely with “Old World” L.L. aethiopica. Often, the onset of ML is heralded by cutaneous lesions which appear several days, weeks, months, or even years before the development of naso-oropharyngeal mucosal lesions. Mucosal disease can be difficult to identify, and most commonly presents as nasal stuffiness, although coryza, epistaxis, hyposmia, and a sensation of pressure or obstruction may be present initially. If not treated early, this can progress to ulcerative destruction of mucosal membranes, especially the nasal septum, and disfigurement [27, 28]. Additionally, ML can lead to significant airway and esophageal complications, including dysphonia, difficulty swallowing, and laryngeal destruction and obstruction.

DIAGNOSIS

Patients with suspected leishmaniasis should undergo an extensive physical examination to determine the clinical syndrome and the extent of disease. For cutaneous disease, this includes a full skin exam to count visible lesions and assess for subcutaneous nodules and lymphadenopathy. For anyone who acquired the infection in the Americas a thorough evaluation of mucosal surfaces, particularly in the nose and mouth, is warranted. If mucosal lesions are suspected or identified, otolaryngology consultation (nasopharyngeal endoscopy) is required to document the extent of oral, nasal, and laryngeal disease [27]. The number, size, and appearance of lesions should be described and documented photographically.

Diagnosis of CL and ML

Patients with skin lesions concerning for CL or ML will require a skin lesion scraping, brushing, aspiration, or biopsy for diagnosis, typically performed by a dermatologist. All samples should be preferentially collected from the upper dermis, peripheral border of active lesions where parasites have the highest concentration. Ideally, multiple samples should be obtained from the same lesion to have enough sample to perform multiple diagnostic tests (thin smear or histopathology with staining, Leishmania culture and Leishmania polymerase chain reaction [PCR]) to increase the ability to identify the organism. If the lesion is covered with exudate, eschar, or devitalized tissue, this should be removed prior to sampling the lesion. Skin scrapings and brushings are ideal for quick evaluation of ulcerative lesions likely to be CL, particularly in children where more invasive diagnostic procedures are challenging. Aspiration should be considered for nodular lesions and ulcerative lesions located in sensitive areas (over the face, genitalia, or small joints) to reduce the risk of scaring [27, 29]. Samples collected by scraping, brushing, or aspiration of the skin lesion can be used for Leishmania culture and Leishmania PCR performed through the CDC reference laboratory [29] or the Canada National Reference Centre for Parasitology (https://www.mcgill.ca/tropmed/national-reference-lab); it is recommended to confirm the reference laboratory testing availability prior to sample collection. Dermal scrapings can also be used to make Giemsa-stained thin smears to enhance organism identification. Conversely, shave or punch biopsies are helpful for confirming the diagnosis in scenarios where leishmanial disease is less certain and other pathology (such as mycobacterial, fungal, or bacterial disease or noninfectious diseases) is being considered. In addition to culture and PCR assays, tissue biopsy allows for histopathologic evaluation with Giemsa, hematoxylin and eosin (H&E) stains and special stains as well as additional cultures to rule out other pathogens. Biopsies are collected from anesthetized (using a small amount of injected lidocaine as high concentrations of lidocaine can inhibit parasite growth) and cleansed (betadine and 70% alcohol) skin. Instructions for performing scrapings, brushings, aspiration, and biopsy can be found on the CDC website(https://www.cdc.gov/parasites/leishmaniasis/resources/pdf/Leishmaniasis_Guide_Collection_2021.pdf). Additionally, the CDC has experts available for consultation regarding appropriate specimen types based on patient characteristics [29]. In addition to conventional Leishmania diagnostic techniques that generally need to be performed in specialized laboratories, a novel CL rapid immunochromatographic assay from InBios (Washington, USA), which detects peroxidoxin antigen from Leishmania amastigotes from skin, has recently been approved by the US Food and Drug Administration (FDA)[30] and is available commercially. Baseline complete blood count (CBC), liver function tests (LFTs), and renal function should be documented prior to starting systemic therapy for CL or ML.

Diagnosis of VL

For a patient presenting with VL, a splenic or bone marrow biopsy is required to identify amastigotes. While globally splenic biopsies are common, in the US bone marrow biopsies are often preferred to avoid the risk of splenic hemorrhage or bowel perforation. The aspirate and biopsy tissue should be processed for histopathology with Giemsa staining, Leishmania culture, and PCR, similar to CL and ML. Enzyme-linked immunosorbent assay and rapid immunochromatographic tests using the recombinant K39 antigen (rk39) are useful, noninvasive, supplemental tools to aid in the diagnosis of VL but typically are unable to differentiate active and resolved infection. The rk39 assay is particularly useful for VL in immunocompetent patients who acquired disease in India, and potentially other regions, although may not be widely available in the US [31]. Additional laboratory testing for VL should include CBC to evaluate for neutropenia, anemia, and thrombocytopenia, LFTs including bilirubin levels and albumin, renal function monitoring as reversible kidney injury has been noted, triglycerides if there is a concern for associated hemophagocytic lymphohistiocytosis and possible evaluation for disseminated intravascular coagulation in severe cases. Abdominal ultrasound or CT scan often shows splenomegaly and, less often, hepatomegaly in cases of VL. Additional laboratory tests and imaging should be guided by the patient’s clinical presentation. Empiric therapy prior to diagnostic confirmation should only be considered in consultation with a specialist in the setting of high probability of VL and clinical deterioration.

TREATMENT BY SYNDROME

The treatment of leishmaniasis in children is dependent on several factors including the clinical syndrome, the Leishmania species, complexity of the disease, and the immunologic function and medical comorbidities of the child (Table 1).

Table 1.

Treatment of Pediatric Patients With Leishmaniasis

Disease	Species	Therapy	Route	Dose and Duration
Cutaneous
Simple	Any	Thermotherapy Cryotherapy (liquid nitrogen) Paromomycin Amphotericin B	Local Local Topical Topical	After application of topical anesthetic: Apply in a grid over the lesion and edge of surrounding skin; leave in place × 30 s with each move. Various regimens; example: freeze with liquid nitrogen × 10–20 s until 1–2 mm of surrounding skin is pale. Thaw 20–60 s, then reapply. Repeat × 3 every 3 weeks. Must be compounded (see Aronson et al. [27] for regimen); apply Q12H × 10 days, rest × 10 days, repeat × 1 or apply once daily × 20 days Early in development; must be compounded
Complex	Any L.L. major	Liposomal amphotericin B Miltefosine (≥12 years and ≥ 30 kg) Alternate (off-label): Pentamidine isethionate Alternate (off-label with very limited data for L.L. major, L. mexicana): Fluconazole Alternate (off-label with very limited data): Ketoconazole	Intravenous Oral Intravenous Oral Oral	3 mg/kg/day ×6–7 doses (on days 1, 2, 3, 4, 5, and 10 or on days 1–7) For 30–44 kg: 50 mg PO Q12H × 28 days For ≥ 45 kg: 50 mg PO Q8H × 28 days 3–4 mg/kg every other day × 3-4 doses (2 mg/kg every other day × 7 doses for L.V. panamensis/guyanensis) Unclear dosing in children; case reports used 3–6 mg/kg/day × 6 weeks, but adult data would suggest that higher doses may be more effective [22]. Typical range for treatment of many invasive fungal diseases in children is 6–12 mg/kg/day (to a maximum of 400—sometimes 800—mg/day). Many toxicities; not recommended
Leishmaniasis recidivans	Typically L.L. tropica	Consult a specialist
Diffuse	Typically L.L. mexicana, L.L. amazonensis, or L.L. aethiopica	Consult a specialist
Disseminated	Typically L.V. braziliensis	Consult a specialist
Mucosal	Typically, L.V. braziliensis, L.V. panamensis, or L.V. guyanensis	*For all: Consider concomitant corticosteroid administration for airway protection if evidence of active mucosal involvement* Amphotericin B deoxycholate (off-label) Liposomal amphotericin B (off-label) Miltefosine (≥12 years and ≥ 30 kg) Alternate (off-label, poor data): Pentamidine isethionate	Intravenous Intravenous Oral Intravenous	0.5–1 mg/kg/day daily or every other day × 20–40 doses 3 mg/kg/day ×10–20 doses (total dose 30-60 mg/kg) For 30–44 kg: 50 mg PO Q12H × 28 days For ≥ 45 kg: 50 mg PO Q8H × 28 days 3–4 mg/kg every other day × 3–4 doses (2 mg/kg every other day × 7 doses for L.V. panamensis/guyanensis)
Visceral
With no alterations of immune function	Any (including L.L. infantum/chagasi, L.L. donovani) Acquired in East Africa L.L. donovani Any	Liposomal amphotericin B Liposomal amphotericin B Miltefosine (≥12 years and ≥ 30 kg) Alternate (off-label, poor efficacy, high rates of adverse events): Pentamidine isethionate	Intravenous Intravenous Oral Intravenous	3 mg/kg/day × 7 doses (on days 1, 2, 3, 4, 5, 14, and 21) (total dose 21 mg/kg) Increased total doses may be required (≥40 mg/kg over treatment course) For 30–44 kg: 50 mg PO Q12H × 28 days For ≥ 45 kg: 50 mg PO Q8H × 28 days 4 mg/kg IV every other day or 3 times weekly × 15–30 doses
In the context of immune suppression	Any (including L.L. infantum/chagasi, L.L. donovani)	Liposomal amphotericin B; consider combination therapy with miltefosine Alternate: Miltefosine(≥12 years and ≥ 30 kg)	Intravenous Oral	4 mg/kg/day × 10 doses (on days 1, 2, 3, 4, 5, 10, 17, 24, 31, and 38) (total dose 40 mg/kg) For 30–44 kg: 50 mg PO Q12H × 28 days For ≥ 45 kg: 50 mg PO Q8H × 28 days

Simple CL: single or few small cutaneous lesions < 5 cm that are not located over cosmetically or functionally important body parts and are not caused by a Leishmania spp. associated with mucosal disease.

Complex CL: multiple cutaneous lesions (≥5 lesions of > 1 cm in diameter), single large lesions (≥5 cm in diameter), lesions over cosmetically or functionally important areas, the presence of subcutaneous nodules or large lymphadenopathy or caused by a Leishmania spp. associated with mucosal disease.

Leishmaniasis recidivans CL: cutaneous lesion which evolves on the periphery of a previously healed localized skin lesion caused by L.L. tropica.

Diffuse/Disseminated CL: wide-spread nodular or plaque lesions typically due to L.L. aethiopica, L.L. mexicana, and L.L. amazonensis or L.V. braziliensis in the setting of cell-mediated immunodeficiency.

Abbreviation: CL, cutaneous leishmaniasis.

Adapted from Aronson et al. [27].

Treatment of CL

A watch-and-wait approach is reasonable for individuals with intact immune function who have a single or few, small lesions (<1 cm) that are not located over cosmetically or functionally important body parts, is not associated with significant lymphadenopathy or subcutaneous nodules (indicative of lymphatic spread) and is not caused by a species associated with a high risk for developing mucosal disease [27]. The choice to forego treatment should be based on a discussion with the child’s family, considering the potential for initial progression of the lesion before spontaneous healing with resultant scarring, the risk of potential evolution to complex disease, and the risks versus benefits of the various treatment options. For children receiving supportive management, regular photography (every month or more often) by the child’s family should be coupled with surveillance visits with a healthcare professional every 3–6 months while the lesion remains active. This level of monitoring will ensure that the child does not develop superinfection from skin flora or have clinical progression that would require the initiation of therapy, such as development of mucosal lesions. The child’s family should also be counseled about the provision of basic wound care for ulcerative lesions (gentle cleansing with soap and water, followed by application of a thin layer of barrier ointment or moisturizer as well as dressing the wound with gauze if actively draining) to encourage healing and prevent secondary infection.

If treatment is desired for “simple” cutaneous lesions, nonpharmacologic interventions such as heat therapy, cryotherapy, photodynamic therapy, and carbon dioxide laser treatments have been shown to be variably effective [27]. Although the success rates of heat and cryotherapy may be lower than most pharmacologic treatments, these interventions are relatively easy to administer, have few potential side effects, and may help to avoid the need for pharmacotherapy [32–36]. Heat or cold therapy over sensitive areas such as the eyes, lips, nose, and genitals should be avoided, as minor local injury may occur. Photodynamic and laser therapies are newer modalities that require specialist care for administration but have been promising in some early trials [27].

Topical creams or gels containing paromomycin or amphotericin B have similarly shown varying degrees of success when employed in the treatment of cutaneous leishmaniasis but may be administered at home and are associated with few adverse effects, thus making them a reasonable alternative option for the treatment of simple cutaneous lesions in children (excluding L. tropica). These formulations are unfortunately not currently commercially available in the US and must be obtained and compounded by a specialty pharmacy if they are to be used. Intralesional pentavalent antimonial should also be considered for Old World cutaneous leishmaniasis but are not currently available in the US. Other intralesional therapies for Old World CL, including amphotericin B and pentamidine, may be available for routine use in the future. Before any topical therapy or intralesional therapy is applied, the child should undergo gentle debridement of the wound and receive treatment for superinfection caused by skin flora (if present), to allow access of the local agent to the lesion and maximize the chances of success [27]. Use of these local agents on the face and genitals should be avoided due to the potential cosmetic implications.

Systemic therapy is generally reserved for complex cutaneous disease but can be considered for simple CL if local therapy is not possible, or if more rapid healing of simple lesions is desired. Complex cutaneous disease is defined as multiple “substantial” lesions (>4 lesions of >1 cm in diameter), single large lesions (≥5 cm in diameter), lesions over cosmetically or functionally important areas (such as the joints, genitalia, or face), or the presence of subcutaneous nodules or large lymphadenopathy [27]. Cutaneous lesions that have failed previous treatment regimens, occur in patients with impaired cell-mediated immunity, or appear to be consistent with uncommon cutaneous syndromes (leishmaniasis recidivans and diffuse/disseminated cutaneous leishmaniasis) should also be approached as complex disease. For complex disease, systemic therapy is recommended. In the US, this consists of either liposomal amphotericin B or miltefosine. Liposomal amphotericin B is administered intravenously for a total of 6–7 doses (cumulative dose of 18–21 mg/kg; although no standard dose regimens have been established), often requires inpatient administration, and has several potential adverse effects, including nephrotoxicity. Miltefosine is an oral medication that is FDA-approved for use in children over 12 years old and weighing > 30 kg who have “New World” cutaneous disease (administered orally twice daily for 28 days). The majority of individuals taking miltefosine report gastrointestinal distress (which can lead to early discontinuation), allergic reactions, transaminitis, and mild reversible kidney injury. Additionally, miltefosine is teratogenic and individuals who have the potential to become pregnant should be counseled about the use of contraception throughout the course of therapy [37]. “Azoles” such as fluconazole have limited use due to lack of clear efficacy but could be considered for disease caused by L. major and L. mexicana. Children with leishmaniasis recidivans, or diffuse or disseminated cutaneous leishmaniasis should be cared for in discussion with a specialist.

Treatment of ML

Cutaneous infections caused by species predisposing to ML (including L.V. braziliensis, L.V. panamensis, and L.V. guyanensis) should be treated to prevent progression to mucosal disease, even if the lesion is healing or already healed at the time of presentation. If the species is unknown, the potential for mucosal disease should be presumed for any child who is likely to have acquired the infection from any country south of Nicaragua in Central and South America, particularly if the child has traveled to or through the “mucosal belt” areas of Bolivia, Peru, and Brazil [27]. For all patients where mucosal involvement is a concern, a detailed nasopharyngeal examination by an otolaryngologist to assess the extent of disease is necessary prior to starting treatment. Amphotericin B is the mainstay of treatment for disease caused by L.V. braziliensis, L.V. guyanensis, and L.V. panamensis in the US; although the deoxycholate form has traditionally been used, data for use of intravenous liposomal amphotericin B are accumulating (3 mg/kg/day for 10–20 doses, total dose 30–60 mg/kg) [38–40]. Children with mucosal disease affecting the larynx are at high risk for complications, including laryngospasm leading to respiratory obstruction with the initiation of antileishmanial therapy. For this reason, they should be admitted for close observation and corticosteroid therapy should be considered at the time of treatment initiation [27].

Treatment of VL

Symptomatic VL requires systemic therapy. Patients who are immunocompromised should be initiated on treatment immediately in order to prevent progression to chronic disease and death. In the US, intravenous liposomal amphotericin B remains the treatment of choice for VL, due to its availability and its demonstrated efficacy against multiple species. The treatment is typically administered over the course of 3 weeks for immunocompetent children (3 mg/kg/daily, total dose 21mg/kg), and over 5 weeks (at varying intervals; 4 mg/kg/daily, total 40mg/kg) if immunosuppressed. Higher cumulative total doses may be needed (>40 mg/kg total dose) if VL is acquired in East Africa. Alternatives treatment options for VL caused by L. donovani include miltefosine, which has been inconsistently efficacious in the treatment of children with VL, possibly due to underdosing based on extrapolation of adult data [41, 42], or intravenous pentamidine, which, because of limited data and the potential for serious side effects with prolonged use, is not a desirable option [43]. Assessment for possible underlying immunologic dysfunction should be performed for any individual with VL, particularly for cell-mediated immunodeficiency caused by HIV or use of immunomodulatory medications, to aid with prognostication and treatment duration [27]. In patients who are diagnosed with VL and have cell-mediated immunosuppression, combination therapy including liposomal amphotericin and miltefosine could be considered.

Posttreatment Monitoring

It is important to note that in all cases of leishmaniasis, the goal of therapy is not necessarily the complete eradication of parasites, as parasitologic cure may not be achieved even with treatment and there is no test of cure. Because of this, relapse is possible in all individuals, particularly in patients who are immunosuppressed as a result of HIV or immunomodulatory medications used in rheumatologic disease, oncologic disease, or transplantation.

Children with CL or ML should be evaluated for clinical evidence of superinfection and treatment failure, which most commonly occurs in the first few months post therapy. The first sign of healing in CL and ML is decrease in perilesional induration, followed by a decrease in the lesion’s diameter. Re-epithelialization occurs over the course of about 3 months, although a paradoxical worsening may sometimes be seen in the first few weeks of therapy. Clinical monitoring by a healthcare professional should continue for 1–year post-healing of lesions caused by Leishmania spp. that are not associated with ML and for a minimum of 2 years (reports of mucosal disease appearing decades after treatment of CL have been reported) post-healing of lesions caused by Leishmania spp. that are associated with ML. Patients should be counseled that the risk of mucosal disease can be life-long. Follow-up exams for CL and ML should include detailed oropharyngeal and nasal examinations to assess for evidence of mucosal involvement at each check-in. If at any point clinical signs or symptoms of the mucosal disease should appear, then immediate fiberoptic evaluation by otolaryngology should be pursued, and treatment should be initiated if mucosal involvement is demonstrated [27].

Individuals who have been treated for VL should be counseled on the signs of disease recurrence, particularly individuals who are immunosuppressed. Monitoring for systemic symptoms such as fever and weight changes as well as physical exam findings including splenomegaly should be completed by a healthcare professional for a minimum of 1-year posttreatment in patients who are immunocompetent, as most therapeutic failures occur in the first 6 months. In individuals that are immunosuppressed, serial follow-up with a health-care provider should continue until immune reconstitution or continue indefinitely in patients who remain immunosuppressed following treatment. Because of the high risk of relapse in patients with HIV with low CD4⁺ T-cell counts (<200 cells/mm³), secondary prophylaxis is recommended until immune reconstitution is achieved with antiretroviral therapy [44–46]. Patients co-infected with VL and HIV should be carefully monitored while receiving prophylaxis as VL relapse remains common in patients with uncontrolled HIV. For patients with immunosuppression not due to HIV, relapse rates are lower, so clinical monitoring alone, without prophylaxis, is sufficient. Although reduction of immunosuppression should be attempted if clinically feasible [27]. A thorough physical exam should be completed in all children from highly endemic locations to assess for leishmaniasis prior to starting immunosuppressive agents.

Patients with previous leishmaniasis should avoid donating blood (particularly patients treated for VL), given the risk of transmission through blood transfusion. Tissue donation may be permissible in select circumstances, but should be thoroughly reviewed prior to organ acceptance [27].

CONCLUSION

The approach to a pediatric patient with leishmaniasis can be challenging. A high suspicion of disease paired with accurate diagnostic techniques to identify Leishmania species are the first steps to providing care to children with leishmaniasis in the US. Treatment options for children are limited by the lack of inclusion of pediatric patients in clinical trials. This has led to the extrapolation of treatment regimens from adult studies. Importantly, new studies have highlighted use of adult dosing in children may lead to under-exposure and poorer outcomes [41, 47]. Additional research is urgently needed to help guide therapy for children and determine appropriate antileishmanial agents, doses, and treatment courses for children with leishmaniasis.

Notes

Financial support. This work was supported by a National Institute of Allergy and Infectious Diseases K08 Grant Number AI143968-01 through the National Institutes of Health.

Potential conflicts of interest. The authors have no conflict of interests.

Contributors: T.E.N., R.M.-B., and J.E.W. conceptualized, wrote, and edited the manuscript.