Leishmaniasis

Author: MBLOGSTU

Introduction

Leishmaniasis refers to the spectrum of clinical disease produced by Leishmania spp. These parasites reside solely within mononuclear phagocytes as intracellular amastigotes in humans and other mammals and as flagellated, extracellular promastigotes in the gut of their sand fly vectors.

The clinical manifestations of disease depend on complex interactions between virulence factors of the infecting Leishmania spp. and the genetically determined, cell mediated immune responses of its mammalian host. Several clinical syndromes are subsumed under the term leishmaniasis—most notably visceral, cutaneous, and mucosal leishmaniasis—resulting from replication of the parasite in macrophages of the mononuclear phagocyte system, dermis, and naso-oropharyngeal mucosa, respectively. These syndromes are caused by about 21 leishmanial species transmitted by some 30 species of phlebotomine sandflies. With some exceptions (e.g., visceral leishmaniasis in India and cutaneous leishmaniasis caused by Leishmania tropica), humans serve as incidental hosts, whereas other mammals (e.g., rodents and canids) are reservoir hosts.

Clinical Syndromes

Visceral Leishmaniasis: Causative species are from the L. donovani species complex (i.e., L. donovani and L. infantum in the Old World and L. chagasi in the New World); also L. tropica (Old World) and L. amazonensis (New World) may be involved.

Cutaneous Leishmaniasis: In the Old World, causative species include L. tropica, L. major, and L. aethiopica (and sometimes L. infantum and L. donovani). In the New World (American), the L. mexicana species complex (especially L. mexicana, L. amazonensis, and L. venezuelensis) and the Viannia subgenus (notably L [V] braziliensis, L [V] panamensis, L [V] guyanensis, and L [V] peruviana) cause disease; other organisms such as L. major-like organisms and L. chagasi are also implicated.

Epidemiology

Leishmania spp. are found on every continent except Australia and Antarctica. They have been reported from 21 countries in the Western Hemisphere and 62 countries in the rest of the world. It is estimated that 350 million people are at risk worldwide. The incidence of cutaneous leishmaniasis is approximately 1.0–1.5 million cases per year, while visceral leishmaniasis is estimated at about 150,000 cases per year.

Epidemiological patterns vary among species and geographic areas. In most endemic regions, leishmaniasis is a zoonosis with reservoirs such as rodents and canines; however, in certain sites—for example, L. (L.) donovani in India—humans serve as the only reservoir. Female sand flies are the vectors: Lutzomyia spp. transmit the disease in the Western Hemisphere, while Phlebotomus spp. transmit it in other parts of the world. Amastigotes can also be transmitted through contaminated blood and, rarely, by person-to-person contact (laboratory infections following accidental needle sticks are documented).

Morphology

Promastigote: The flagellated form of Leishmania, which can be found in sandflies and in culture. It typically measures 15–20 μm by 1.5–3.5 μm and has a flagellum 15–28 μm in length.

Amastigote: The non-flagellated, tissue form that replicates within macrophage phagosomes in mammalian hosts; these are typically 2–4 μm in diameter.

Pathogenesis

In cutaneous leishmaniasis, the disease manifestations typically occur at the site where promastigotes are inoculated into the skin. Although the exact sequence in humans remains undefined, histopathological studies in hamsters inoculated subcutaneously with cultured L. (L.) donovani promastigotes suggest that some parasites are killed by neutrophils, while others are phagocytosed by mononuclear phagocytes, convert to amastigotes, and multiply. Subsequent recruitment of additional monocytes leads to further infection.

In cutaneous disease, early lesions are characterized by amastigote-filled macrophages, followed by the development of a necrotizing granulomatous response with focal necrosis and ulceration. The mechanism of tissue necrosis is believed to be immune-mediated.

In visceral leishmaniasis, most infected individuals remain asymptomatic and self-resolving. When symptoms do occur, amastigotes disseminate to phagocytic cells in the liver, spleen, bone marrow, and other organs, leading to massive splenomegaly and hepatomegaly.

Clinical Manifestations

Cutaneous Leishmaniasis

Simple Cutaneous Leishmaniasis

In simple cutaneous leishmaniasis, lesions develop at the sites where promastigotes are inoculated by sand fly bites. Lesions may be solitary or multiple, with incubation periods ranging from 2 weeks to several months (rarely up to 3 years). They typically begin as papules that enlarge and, in most cases, ulcerate. Many lesions develop a "pizza-like" appearance—with a circular, raised outer border, a beefy red, granulating base, and an overlying yellow exudate (referred to as “wet” lesions). “Dry” lesions tend to be smaller with minimal ulceration and an overlying crust.

Diffuse Cutaneous Leishmaniasis

Diffuse cutaneous leishmaniasis is characterized by the development of plaque-like or nodular lesions on the face or other exposed areas, which spread gradually without ulceration. Biopsies reveal numerous amastigote-filled macrophages, while the leishmanin skin test is negative, and peripheral blood mononuclear cells fail to proliferate or produce IFN-γ or IL-2 in response to leishmanial antigens.

Leishmaniasis Recidiva

Leishmaniasis recidiva is a chronic, localized process associated with L. (L.) tropica in the Middle East. Lesions expand slowly, often persisting for years with central healing and peripheral expansion. They typically occur on the face or other exposed areas, and biopsies show a chronic granulomatous response with few parasites.

Mucosal Leishmaniasis (Espundia)

In a small percentage of cases, healing of cutaneous lesions—usually due to L. (V.) braziliensis or occasionally other Leishmania (V.) spp.—is followed months to years later by the development of destructive mucosal lesions. The nose is frequently involved, presenting with nasal stuffiness, discharge, or discomfort. Progressive septal destruction can result in nasal collapse and a “tapir” nose, while destructive lesions may also affect the lips, oral pharynx, or larynx, leading to significant disfigurement.

Visceral Leishmaniasis (Kala-azar)

Visceral leishmaniasis is primarily caused by Leishmania (L.) donovani, L. (L.) chagasi, and L. (L.) infantum, although occasionally other species (e.g., L. (L.) amazonensis or L. (L.) tropica) are isolated. It most commonly affects young children in highly endemic areas. Patients present with a subacute onset of fever, weakness, fatigue, weight loss, splenomegaly, and hepatomegaly. In some cases, the onset is acute and may mimic malaria. Fever patterns may be intermittent, remittent with twice-daily spikes, or continuous. Progressive enlargement of the liver and spleen is typical; in Indian patients, hyperpigmentation is observed—a hallmark that gave rise to the term “kala-azar” (black fever).

Post-kala-azar dermal leishmaniasis occurs in a subset of patients after therapy. In Africa, lesions typically appear at the end of treatment or within a few months and persist for several months, whereas in India they may emerge up to 2 years after treatment and last for many years.

Laboratory Diagnosis

The laboratory diagnosis of visceral leishmaniasis is based on finding amastigotes in specimens such as:

• Material aspirated from the spleen, bone marrow, or an enlarged lymph node
• Nasal secretions
• Peripheral blood monocytes, and less commonly neutrophils (using buffy coat preparations). In patients co-infected with HIV, amastigotes may be found more frequently in blood monocytes, neutrophils, and lymph node aspirates.

When biopsies, aspirates, or touch preparations are stained using a Wright–Giemsa method, amastigotes display light blue cytoplasm, an eccentrically located red nucleus, and an intensely stained, small red kinetoplast.

Culture: Leishmania spp. can be isolated in culture. Specimens such as biopsies from cutaneous lesions or splenic/bone marrow aspirates from visceral leishmaniasis patients may be cultured in Novy, Nicolle and MacNeal’s (NNN) medium.

Detection of Anti-Leishmanial Antibodies: In visceral leishmaniasis, both specific antibodies and non-specific polyclonal IgG and IgM are produced. Techniques used include:

• Direct Agglutination Test (DAT)
• rK39 dipstick to detect anti-rK39 antibody
• Katex test—a latex agglutination test that detects leishmanial antigen in urine
• Formol Gel (aldehyde) Test—which, despite its low reliability, is used in some remote areas due to its simplicity and low cost. It becomes positive approximately 3 months after infection and turns negative about 6 months after successful treatment.

Diagnosis of Cutaneous and Mucocutaneous Leishmaniasis: This primarily involves:

• Detecting amastigotes in smears from infected ulcers or nodules (note that in mucocutaneous leishmaniasis, the parasites may be scarce)
• Culturing ulcer material and examining the cultures for promastigotes
• Leishmanin Skin Test (Montenegro Reaction): using an antigen prepared from killed culture forms (promastigotes) of L. braziliensis, L. mexicana, or L. tropica, at a concentration of 10×10^6 parasites per ml.

Treatment

Treatment options for leishmaniasis include:

• Pentavalent antimony
• Amphotericin B deoxycholate
• Ketoconazole
• Itraconazole
• Dapsone