Leishmania

Leishmania comprises a genus of obligate intracellular protozoan parasites transmitted by sandflies, producing three principal clinical syndromes depending on the infecting species, the parasite's tissue tropism, and the host immune response.

Visceral leishmaniasis (kala-azar) is the most severe form. It is caused principally by Leishmania donovani (Indian subcontinent, East Africa) and Leishmania infantum (Mediterranean basin, Latin America, where it is also referred to as Leishmania chagasi).

The parasite disseminates to and replicates within the reticuloendothelial system, infecting macrophages throughout the spleen, liver, bone marrow, and lymph nodes. Untreated visceral leishmaniasis is fatal in the large majority of symptomatic cases, making it the deadliest of the three forms.

Classic features of visceral leishmaniasis are:

• Prolonged fever.
• Marked splenomegaly (often massive) with lesser hepatomegaly.
• Progressive pancytopenia, from marrow infiltration, splenic sequestration, and hypersplenism.
• Weight loss and wasting.
• Hypergammaglobulinaemia with a reversed albumin-to-globulin ratio.

Skin darkening is a recognised feature in some endemic populations, particularly on the Indian subcontinent. It gives kala-azar its name, meaning "black fever" or "black sickness".

Cutaneous leishmaniasis is the most common clinical form worldwide. Many species cause it, depending on region:

• Leishmania major and Leishmania tropica (Old World, Middle East, North Africa, Central Asia).
• Leishmania mexicana and Leishmania braziliensis (New World, Central and South America). Braziliensis is more closely associated with mucocutaneous disease.

Infection remains localised to the skin at or near the sandfly bite site. A papule enlarges and typically ulcerates over weeks to months. The ulcer is painless in most cases, with raised, indurated borders often described as volcano-shaped. It heals slowly over months to years, leaving a disfiguring scar.

Multiple bites can cause multiple lesions. Satellite lesions or regional lymphadenopathy may develop.

Mucocutaneous leishmaniasis is a New World syndrome, most strongly associated with Leishmania braziliensis (and related species within the Viannia subgenus). Parasites spread from the primary cutaneous lesion by lymphatic or haematogenous dissemination to the nasopharyngeal and oral mucosa. This typically presents months to years after apparent healing of the original skin lesion.

Progressive, destructive granulomatous inflammation of the nasal septum, palate, and pharyngeal tissue produces severe tissue destruction. This includes nasal septal perforation and collapse, producing the classically described "tapir nose" or "espundia" deformity.

The disease can extend to the larynx, with risk of airway compromise and disfigurement. Unlike cutaneous disease, mucocutaneous leishmaniasis does not spontaneously resolve and requires treatment.

Sandfly vector. Female phlebotomine sandflies (Phlebotomus species in the Old World, Lutzomyia species in the New World) are the obligate biological vector. The sandfly acquires infection during a blood meal on an infected human or animal reservoir host.

Many Leishmania species are zoonotic. Reservoirs include rodents, canids (particularly domestic dogs), and other mammals, depending on species and region.

Promastigote. Within the sandfly midgut, ingested amastigotes transform into promastigotes. This is the extracellular, flagellated, motile form, with an elongated spindle shape and a single anterior flagellum. Promastigotes multiply by binary fission within the sandfly gut and migrate to the proboscis. There they mature into the infective metacyclic promastigote form, ready for transmission at the next blood meal.

Amastigote. Promastigotes are inoculated into the human host's skin during a sandfly bite. Host macrophages (and other mononuclear phagocytic cells) phagocytose them, and they transform into amastigotes. Amastigotes are oval and non-flagellated (or have only a rudimentary, non-protruding flagellum). They are the obligate intracellular form.

Amastigotes replicate by binary fission within the macrophage's phagolysosome. This is a hostile intracellular compartment that the parasite has specifically adapted to survive and exploit.

Amastigote-laden macrophages eventually rupture. The released organisms infect further macrophages locally (cutaneous disease) or disseminate via blood and lymphatics to distant reticuloendothelial tissue (visceral disease). A feeding sandfly ingests circulating or dermal amastigotes from an infected host, completing the cycle.

Macrophage infection. The central pathogenic event in all forms of leishmaniasis is survival and replication of amastigotes within host macrophages. The normal function of these cells includes destroying intracellular pathogens.

Leishmania has evolved specific mechanisms to resist macrophage killing:

• Interference with the oxidative burst.
• Modulation of phagolysosomal maturation and acidification.
• Manipulation of macrophage signalling to favour a less effective immune response.

The host immune response largely determines the outcome of infection: self-limited cutaneous disease, chronic destructive mucocutaneous spread, or overwhelming visceral dissemination.

A strong, appropriately polarised cell-mediated (Th1-type) response tends to control or clear infection. Activated macrophages produce nitric oxide and other leishmanicidal mechanisms under the influence of interferon-gamma.

A Th2-skewed or otherwise ineffective response permits progressive parasite multiplication and dissemination. This is central to why visceral leishmaniasis behaves as an opportunistic, often fatal disease in individuals with impaired cell-mediated immunity. In advanced HIV infection, it can present atypically and has high relapse rates despite treatment.

Tissue microscopy. Direct visualisation of amastigotes within macrophages on Giemsa-stained smears or biopsy sections remains a mainstay of diagnosis. In tissue, amastigotes seen microscopically are referred to as Leishman-Donovan bodies.

In visceral disease, the options are:

• Splenic aspirate, which has the highest sensitivity but carries a real risk of haemorrhage, given the vascularity and often massive size of the spleen.
• Bone marrow aspirate, more commonly used as a safer alternative, with somewhat lower but still substantial sensitivity.
• Lymph node aspirate, a further option.

In cutaneous and mucocutaneous disease, examine tissue scraping, punch biopsy, or aspirate from the active edge of the lesion for amastigotes. The necrotic centre yields fewer organisms.

Culture. Aspirated or biopsied material can be cultured on specialised media (such as Novy-MacNeil-Nicolle, NNN, medium). The organism transforms into promastigotes in vitro, which confirms the diagnosis and permits species identification. Culture is slower than direct microscopy and needs specific laboratory capacity that is not universally available.

Molecular methods. PCR-based testing on tissue, blood, or aspirate specimens has high sensitivity and specificity. It also allows species identification, which has direct clinical relevance, because treatment choice and the risk of mucocutaneous progression differ by species.

This matters particularly in New World cutaneous disease. Distinguishing Leishmania braziliensis (higher mucocutaneous risk) from other New World species influences management decisions.

Serology. Serology is useful in visceral leishmaniasis, where parasite burden and antibody response are typically high. It is of limited value in cutaneous disease, where humoral response is generally poor and cross-reactivity with other infections can reduce specificity.

Skin testing. The delayed-type hypersensitivity skin test (the leishmanin or Montenegro skin test) reflects cell-mediated immune response. It is characteristically negative in active visceral disease, reflecting the impaired Th1 response that permits dissemination. It becomes positive after successful treatment or in localised cutaneous disease. It is therefore a marker of immune status and past or resolving infection, not an acute diagnostic test.