Leishmania Species (Leishmaniasis)

Description of the Pathogen

The genus Leishmania comprises vector-borne protozoan parasites that cycle asexually between the digestive tract of the sand fly as a motile flagellated promastigote and, in a wide range of vertebrate hosts (e.g., rodents, canids, hyrax, humans), as an immotile intracellular amastigote ( Fig. 267.1 ). Infection can be either zoonotic or anthroponotic (when humans serve as reservoir) and occurs when a female sand fly ( Fig. 267.2 ) takes a blood meal and introduces infective metacyclic promastigotes into a vertebrate’s skin, where they are phagocytosed by macrophages and dendritic cells. The parasites replicate in the reticuloendothelial system in phagolysosomes while evading or disabling host defenses; host cells ultimately rupture and release amastigotes, which infect other phagocytic cells ( Fig. 267.3 ). In addition, parasites disseminate through regional lymphatics and vascular channels.

The genus Leishmania is divided into subgenera: Leishmania , distributed worldwide; Viannia , limited to Central and South America; and Mundinia ( Table 267.1 ). Species can be categorized by parasite isoenzymes (zymodemes), but current taxonomy increasingly relies on molecular analysis with species-specific oligonucleotide primers or mass spectrometry. ^,

Pathogenesis and Immunity

The virulence of a specific parasite for a specific host depends on many interacting variables. Parasite factors include inoculum size, genetically determined subspecies or strain variability that influences pathogenicity, tissue tropism, and the endosymbiont Leishmania RNA virus. Host factors include immune defects, nutritional status, extremes of age, and comorbidities. Sand fly factors such as the maxadilan content of Lutzomyia saliva, a vasodilatory protein that also otherwise facilitates infection, and gram negative bacilli that activate the human inflammasome to produce interleukin (IL)-1β are also associated with pathogenicity. Host immune responses acquired before infection directed against sand fly saliva impede Leishmania infection. ^,

Despite the fact that each Leishmania sp. usually causes a specific clinical syndrome (i.e., visceral leishmaniasis [VL], cutaneous leishmaniasis [CL], or mucosal leishmaniasis [ML]), any species can cause other clinical syndromes. Infection occurs when the parasite is able to overcome or inhibit protective host cell-mediated immunity, expressed predominantly by a Th1 response driven by interferon (IFN)-γ, IL-2, and IL-12. At the cellular level, IFNγ induces macrophage l -arginine−dependent nitric oxide and superoxide production. A predominantly Th2 host response or Leishmania inhibition of the host Th1 response usually facilitates infection. Abnormal host cell−mediated immune responses increase infection rates, disease severity, and atypical manifestations. Histopathology of affected tissue shows mixed acute and chronic infection and granulomas with epithelioid giant cells, with or without parasites. With clinical cure, the host develops species-specific immunity dependent, in part, on lifelong persistence of viable intracellular parasites and a Th1 cellular response. Memory T lymphocytes, even in the absence of persistent parasites, and CD8 ⁺ T lymphocytes also may play a role. In VL, a positive skin test response is present concomitantly with clinical cure. Antibodies directed against the parasite are not protective, although their presence may aid in diagnosis.

Epidemiology

Leishmaniasis is a complex of diseases transmitted by a sand fly bite. Human infection is caused by >23 species of Leishmania with >90 sand fly subspecies that are proven or likely vectors. Proven vectors of human disease are the genus Phlebotomus in the Old World and Lutzomyia in the New World ( Table 267.1 ). Leishmaniasis generally is a zoonosis with ecologic links between a specific animal reservoir and sand fly subspecies. Anthroponotic transmission is seen in urban L. tropica cutaneous infections in Afghanistan. Anthroponotic transmission of L. donovani visceral infection occurs in India, Nepal, and Bangladesh, whereas mixed zoonotic and anthroponotic L. donovani transmission occurs in East Africa. Female sand flies are usually nocturnal feeders, but if disturbed, they may feed during the day. Transmission is seasonal, and sand flies are poor fliers, so hyperendemic transmission areas occur close to mammalian reservoirs. Other uncommon modes of transmission include intravenous drug use, blood transfusion, organ transplantation, occupational needle stick, laboratory accident, maternal-fetal transmission, and possibly sexual transmission.

The World Health Organization (WHO) reports 700,000 to 1 million new cases of leishmaniasis annually, with 80% of cases being cutaneous disease. Nearly a 60% decrease in VL has been noted, especially in the Indian subcontinent. In 2018 most VL cases were reported from Brazil, China, Ethiopia, India, Iraq, Kenya, Nepal, Somalia, South Sudan, and Sudan ( Fig. 267.4 ). VL due to L. infantum occurs primarily in the Mediterranean, Middle East, Afghanistan, Brazil, Iran, Iraq, and Pakistan. ^, In contrast, the Global Burden of Disease study estimated a 2015 prevalence of 3.9 million CL cases, with a 174% increase from 1990–2013. ^, Most CL cases are reported from Afghanistan, Algeria, Bolivia, Colombia, Iran, Iraq, Pakistan, Syria, and Tunisia ( Fig 267.4 ). ^,

Leishmaniasis is a neglected tropical disease; globally, it is strongly associated with social determinants of poverty and limited resources are available for disease control, diagnosis, and treatment. The socioeconomic burden of leishmaniasis is great. VL is the third most common parasitic cause of death in the world behind only malaria and trypanosomiasis. A disproportionate number of children compared with immunocompetent adults are infected with VL and Old World CL. Contributing factors include higher rates of malnutrition, lack of prior exposure and acquired immunity, and a less mature immune system. Worldwide migration, poverty, lack of adequate control measures, and immunosuppressing conditions are driving an increasing incidence of VL. ^,

Sporadic leishmaniasis can affect people of all ages and can occur when susceptible people (e.g., tourists, migrants) enter an endemic area. Outbreaks have been associated with movement of large numbers of susceptible people (e.g., agricultural workers, refugees, military personnel) into endemic areas. ^, Among travelers, imported CL cases have increased since the mid-2000s. CL accounts for almost 20% of dermatologic conditions in returning travelers from Central and South America, especially Bolivia, Costa Rica, and Peru. In one report, Old World CL due to L. infantum was associated with Mediterranean coastal travel and New World CL due to Viannia spp. was reported in backpackers or soldiers.

Clinical Manifestations

Cutaneous Leishmaniasis

CL should be suspected when a person has a chronic, usually painless, nodular or ulcerative lesion on exposed skin and a history of residence in or travel to an endemic area. Nuances of childhood cases are shown in Box 267.1 . The incubation period after sand fly bite is between 2 weeks and many months, sometimes even years. An erythematous macule appears first, gradually becoming an inflammatory papule with progressive induration (with or without superficial scaling). As inflammation increases, the papule becomes nodular, often ulcerating, and with a raised border. Lesion morphology is highly variable and includes plaques and psoriasiform or verrucous lesions. Size can vary from <1 cm to 10 cm. Satellite lesions, hyperkeratotic eschars, fibrinous exudates, sporotrichoid (lymphangitic) spread, and regional lymphadenopathy also occur. Lesions usually are painless unless secondarily infected. ^, Resolution with scarring (usually described as paper-like with thin skin) is the rule, taking from months to years. Facial lesions can be quite disfiguring and may involve mucosae contiguous with skin (sometimes resembling ML). Lesions overlying joints may heal poorly.

BOX 267.1

Special Comments Regarding Leishmaniasis in Children

General

• Children comprise a disproportionately larger part of the total disease burden, including visceral leishmaniasis (VL) due to L. infantum (syn. chagasi ) , and some cutaneous leishmaniasis (e.g., Old World cutaneous leishmaniasis [CL]).

• Children have fewer comorbidities and tolerate systemic therapy better than adults, with fewer and milder adverse effects.

• Systemic treatment of children’s leishmaniasis may yield lower cure rates than adults due to pharmacokinetic differences (e.g., increased drug clearance).

• Scarring and disfigurement, especially facial, can result in social stigmatization that may be highly damaging, especially but not exclusively, for young women and girls.

• For prevention of sand fly bites, use recommended insect repellents and permethrin-treated fine-mesh bed nets and clothes.

Cutaneous Leishmaniasis

• Children have facial lesions more often than adults do.

• Most children in Old World-endemic areas are infected at 2–3 years of age.

• Local therapy (e.g., thermotherapy, intralesional injection) often is painful or traumatic and may require multiple sessions; anesthesia or sedation may be required.

Visceral Leishmaniasis

• Mortality of treated VL in endemic countries ranges from 3%–10%, with a somewhat better prognosis for children. However, children aged <6 months and adults aged ≥65 years have the highest mortality rates.

• Asymptomatic or oligosymptomatic infections (which can mimic many other pediatric diseases) occur variably by location and may or may not progress to overt disease.

• Congenital infection occurs rarely.

• Hemophagocytic lymphohistiocytosis (HLH) can be induced by VL, and VL should be considered in any patient with HLH residing in or having visited a VL-endemic area.

• The sensitivity of bone marrow aspiration for diagnosing VL in children is approximately 90%, better than for adults (40%–70%).

• Pediatric-specific dosing regimens for amphotericin products may be required.

• Miltefosine is problematic for young children because it is only available as capsules, weight-based dosing for small children may be insufficient, and it is not yet approved by the US Food and Drug Administration (FDA) for children aged <12 years or weighing <30 kg.

CL in the normal host most often is localized, but the interplay between host and parasite can lead to a wide spectrum of manifestations, such as inflammatory oligoparasitic lesions (e.g., leishmaniasis recidivans) or hyperparasitic, less inflammatory, nonulcerating, even coalescent lesions (e.g., diffuse CL) ( Fig. 267.5 ). CL in immunocompromised people, especially in those with abnormal cell-mediated immunity, may have an especially prolonged course, more severe or unusual cutaneous lesions, or occasionally become visceralized. ^,

The multiple clinical syndromes associated with the many geographically diverse species of Leishmania are listed in Table 267.1 . Old World CL occurs widely in the Middle East, the Mediterranean, Asia, Africa, and the Indian subcontinent. The parasites responsible usually are L. major, L. tropica, and L. aethiopica, but also L. infantum , L. donovani , and, rarely, L. enriettii . Leishmaniasis recidivans is almost always due to L. tropica , mostly on the face, usually at the edge of a healed CL scar. The lesions include nodules, papules, and shallow ulcers and can wax and wane over years, are difficult to treat, and are oligoparasitic and inflammatory. ^,

New World CL is widespread in Latin America and is caused by a number of species from both Viannia and Leishmania subgenera ( Table 267.1 ). In addition, L. infantum (syn. chagasi ) also can cause cutaneous disease. As in Old World CL, the primary manifestation is localized CL, but diffuse CL does occur ( L. mexicana and L . amazonensis ) as does disseminated CL ( L.V. braziliensis ). ^,