Leishmania/Leishmaniasis

Leishmania species are obligate intracellular parasites that are transmitted by an infected sandfly. The disease is endemic to Asia, the Middle East, Africa, the Mediterranean, and South and Central America. Clinical presentation varies, dependent on the pathogenicity of the species and the host’s immune response. The mildest form is cutaneous leishmaniasis (CL), characterized by painless skin ulcers. The mucocutaneous type involves more tissue destruction, causing deformities. Visceral leishmaniasis (VL), the most severe form, presents with hepatosplenomegaly, anemia, thrombocytopenia, and fever. Management is based on the clinical severity and patient’s immune status. Some cutaneous lesions spontaneously resolve or require local therapy. Systemic treatment (amphotericin B), however, is needed for VL.

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General Characteristics

Leishmania spp.

  • Structure: 
    • Unicellular, with slender body and polar flagellum (depending on form)
    • Species morphologically similar, with differing molecular features
  • 2 forms:
    • Promastigote: extracellular flagellate organism in the phlebotomine sandfly 
    • Amastigote: obligate intracellular non-flagellate ovoid organism in human or animal host
  • Associated diseases:
    • Cutaneous leishmaniasis (CL), also called:
      • Oriental sore
      • Chiclero ulcer
      • Baghdad boil
    • Mucocutaneous or mucosal leishmaniasis (also called espundia)
    • Visceral leishmaniasis (VL; also called kala-azar or “black fever”)

Clinically relevant species

  • Leishmania donovani (L. donovani), L. infantum (VL)
  • L. tropica, L. major (Old World CL)
  • L. mexicana (New World CL)
  • L. braziliensis, L. panamensis, and L. peruviana (mucocutaneous leishmaniasis)

Epidemiology

  • Global prevalence: 4.8 million
  • 20–30,000 deaths per year
  • Geographic areas affected:
    • Old World leishmaniasis:
      • Species found in Africa, Asia, and Europe
      • Associated with cutaneous or visceral disease
    • New World leishmaniasis:
      • Species found in the Americas (predominantly Central and South America)
      • Associated with cutaneous, mucocutaneous, and visceral disease

Pathogenesis

Reservoirs and transmission

  • Reservoirs: mammals (e.g., dogs, rodents, and foxes)
  • Transmission: 
    • Bite of an infected sandfly (vector):
      • Anthroponotic (from infected humans to healthy humans)
      • Zoonotic (from infected animal reservoir to healthy humans) 
    • Human-to-human transmission can also occur via shared infected needles.

Pathophysiology

In the sandfly:

  • Nocturnal sandflies acquire amastigotes from a zoonotic host.
  • In the gut, the amastigotes develop into flagellated promastigotes and replicate.
  • Promastigotes eventually migrate into the proboscis.
  • When the sandfly bites a human, the promastigotes are then injected into the skin.

In humans:

  • Promastigotes: 
    • Are phagocytosed by macrophages 
    • Lose the flagella and form amastigotes
  • Amastigotes multiply within the phagolysosome, seen in smears as a distinctive form: Leishman-Donovan bodies.
  • Evasion and survival facilitated by:
    • Surface lipophosphoglycan (↓ complement attachment, ↑ complement inactivation)
    • Membrane acid phosphatase: ↓ macrophage oxidative burst and lysosomal enzymes
    • Suppression of CD4+ T helper lymphocytes
  • Multiplying amastigotes lead to cell rupture:
    • Spreading the organisms to other cells
    • Allowing the organism to be possibly taken up by a feeding sandfly

Disease process

  • Depends on the pathogenicity of the species and the host’s immune response
  • Localized CL:
    • Species elicit adequate cellular immune response (CD4+ T cells) leading to macrophage release of toxic nitric oxide, reducing the parasites.
    • Disease leads to eventual spontaneous cure with lesions disappearing.
  • Mucocutaneous or mucosal leishmaniasis:
    • Cutaneous sequence similar to CL, but followed by secondary lesions after weeks to months
    • Tissue destruction noted especially in nasopharyngeal structures
  • VL:
    • Other strains fail to elicit a cellular immune response, resulting in disseminated infection.
    • Spread from bloodstream to reticuloendothelial cells: liver, spleen, bone marrow, and lymph nodes
Leishmaniasis life cycle

The life cycle of the parasites from the genus Leishmania, the cause of the disease leishmaniasis:

On the left side (start at the bottom): Sandfly acquires amastigotes from an infected mammal. Amastigotes transform into extracellular promastigotes that multiply in the midgut. Eventually, the promastigotes migrate to the sandfly proboscis, ready to be transferred to a host when the sandfly bites.
On the right side (start at the top): Promastigotes are transferred to mammals, and are phagocytosed by macrophages. In the cell, promastigotes transform into amastigotes and multiply. Affected cell ruptures and amastigotes spread to infect other cells.

Image: “Leishmaniasis life cycle diagram” by Mariana Ruiz Villarreal. License: Public Domain

Clinical Presentation

Cutaneous leishmaniasis (CL)

  • Causative strains:
    • L. tropica
    • L. mexicana
    • L. major
  • Incubation period: weeks to months
  • Spectrum of cutaneous disease:
    • Localized CL: 
      • Most common 
      • A single or multiple painless, pink papule(s) at the site of the bite 
      • Affects exposed areas
      • Lesions enlarge and ulcerate centrally, covered with a hyperkeratotic eschar or white fibrinous material.
      • Can have satellite lesions
      • Often heals with a depigmented scar after months
    • Leishmaniasis recidivans (LR):
      • Associated with L. tropica
      • Papules develop around the scar of a healed primary lesion. 
      • Can appear following trauma in the same healed lesion many years after 
    • Diffuse CL (DCL):
      • A localized lesion develops, but no ulceration  
      • Amastigotes spread to other areas of the skin, leading to nodules or plaques.
      • Affects the face and extensor limb surfaces, even the entire body 
      • At-risk patients have a defect in the cell-mediated immune response (biopsy shows minimal lymphocytic reaction).

Mucocutaneous leishmaniasis

  • Causative strains: 
    • L. braziliensis
    • L. panamensis
    • L. peruviana
  • Incubation period: weeks
  • Signs and symptoms:
    • Lesions can be single or multiple.
    • Destructive painful mucosal lesions affect the nasopharyngeal and palatine mucosal tissues (occasionally, the perineum).
    • May completely destroy the nasal septum
    • Presents with mucosal secretions, deformities, and pain

Visceral leishmaniasis (VL)

  • Causative strains:
    • L. donovani
    • L. infantum
  • Incubation period: 2–6 months (but can reach up to 24 months)
  • Signs and symptoms:
    • Spread occurs from the initial lesion to reticuloendothelial cells including the spleen, liver, lymph nodes, and bone marrow. 
    • Systemic symptoms:
      • Fever, rigor, and chills
      • Anorexia
      • Weight loss
    • Skin hyperpigmentation
    • Lymphadenopathy
    • Abdominal discomfort (secondary to hepatosplenomegaly)
    • Pallor (secondary to anemia resulting from splenic sequestration or bone marrow suppression)
    • Petechial rash and bleeding (from thrombocytopenia and/or pancytopenia from bone marrow dysfunction)
    • In advanced disease: ascites and edema (from hypoalbuminemia)
    • Post-Kala-Azar dermal leishmaniasis (PKDL):
      • In India, Sudan, and other East African countries, some develop skin lesions during VL or after treatment of VL. 
      • Presents with hypopigmented macules, papules, or nodules; possible infiltration of the skin and oral mucosa

Diagnosis

General diagnostic tools

  • Relies on history (including travel) and clinical findings
  • Specimens:
    • CL: skin lesion aspirate, scraping, or biopsy
    • Mucocutaneous leishmaniasis: mucosal biopsy, dental scrapings
    • VL: aspirates from bone marrow, liver, lymph nodes, or spleen
  • Tests:
    • Histopathologic examination of the specimen:
      • Use of Giemsa’s, Leishman’s, or Wright’s stains
      • Visualization of amastigotes or Leishman-Donovan bodies (round organisms with nucleus, cytoplasm, and rod-shaped kinetoplast)
    • Culture of tissue aspirates (results in 1–3 weeks)
    • Molecular testing (requires specialized laboratories): polymerase chain reaction (PCR)
    • Skin test (Montenegro skin test):
      • Injection of killed promastigotes; ≥ 5-mm induration is positive
      • Use in CL (except diffuse form)
      • Positive test: present or past (resolved) infection
      • Negative in immunosuppressed patients, active VL (becomes positive after treatment) 
      • Not available in the United States

Additional tests for VL

  • Serology or detection of antibodies:
    • Enzyme-linked immunosorbent assay (ELISA)
    • Indirect immunofluorescent antibody test (IFAT)
  • Rapid immunochromatographic test:
    • Detects antibodies to a recombinant antigen rK39 (39 amino acids in the kinesin region of L. infantum)
    • Used in the field (result noted in 15 minutes)
    • Fingerprick blood or serum
    • Positive for years, so not used for detection of relapse or cure
  • Complete blood count: ↓ white blood cell, hemoglobin, platelets
  • Abnormal liver function tests

Management

Cutaneous leishmaniasis

  • Most uncomplicated lesions (small (< 1-cm), single lesion in immunocompetent patients) resolve spontaneously.
  • Treatment accelerates healing, and decreases scarring and superinfection.
  • Local treatment recommended in:
    • Persistent or spreading lesions
    • Lesions in the face or hands
  • Local treatment options:
    • Cryotherapy 
    • Local heat therapy
    • Intralesional pentavalent antimonial drugs
    • Topical paromomycin
  • Systemic treatment recommended in:
    • DCL, LR
    • Large lesion (≥ 5 cm) 
    • Multiple (> 4) cutaneous lesions
    • Subcutaneous nodules
    • Immunosuppressed patients with CL
    • Failed local therapy
  • Systemic treatment options:
    • Miltefosine
    • Azoles
    • Amphotericin deoxycholate
    • Liposomal amphotericin B
    • Pentavalent antimonial drugs (sodium stibogluconate, meglumine antimoniate)
    • Pentamidine

Mucocutaneous leishmaniasis

  • Pentavalent antimonial drugs (with pentoxifylline)
  • Liposomal amphotericin B
  • Miltefosine

VL

  • Liposomal amphotericin B (preferred in the Americas and Europe)
  • Pentavalent antimonial drugs
  • Miltefosine
  • Treat HIV, if present, when tolerated by patient.
  • Prognosis: mortality rate of 75%–90% without treatment

Prevention

  • Reduce sandfly burden by spraying living/sleeping areas with insecticide.
  • Minimize exposure to sandflies:
    • Reduce outdoor time from dawn to dusk.
    • Use insecticide-treated bed nets.
    • Apply insect repellent to exposed skin.

Comparison of Flagellated Protozoa

Table: Comparison of clinically relevant flagellated protozoa
GiardiaLeishmaniaTrypanosomaTrichomonas
Characteristics
  • 4 pairs of flagella
  • Ovoid shape
  • Adhesive disc
  • Anaerobe
  • Antigenic variation
  • Single, polar flagellum
  • Slender, elongated body
  • Single, polar flagellum
  • Undulating membrane
  • Thin, irregularly shaped
  • Antigenic variation
  • 5 flagella
  • Undulating membrane
  • Ovoid shape
  • Facultative anaerobe
Forms
  • Cyst
  • Trophozoite
  • Promastigote
  • Amastigote
  • Trypomastigote
  • Amastigote
  • Epimastigote
  • Trophozoite
  • No cyst form
Transmission
  • Waterborne
  • Fecal-oral
  • Vector (sandfly)
  • Human to human
  • Zoonotic (rodents, dogs, foxes)
  • Vector (tsetse fly, kissing bug)
  • Blood transfusion
Sexually transmitted
ClinicalGiardiasisLeishmaniasis
  • African sleeping sickness
  • Chagas disease
Trichomoniasis
Diagnosis
  • ELISA
  • DFA
  • NAAT
  • Stool microscopy
  • Blood smear
  • Biopsy
  • PCR
  • Leishmanin skin test
  • Antibody titers
  • Blood smear
  • Antibody titers
  • Xenodiagnosis
  • Microscopy of vaginal secretions
  • NAAT
  • Urine or urethral swab culture
Treatment
  • Metronidazole
  • Tinidazole
  • Nitazoxanide
Depends on the clinical syndrome:
  • Amphotericin B
  • Pentavalent antimonials
  • Miltefosine
Depends on the clinical disease:
  • Suramin
  • Pentamidine
  • Melarsoprol
  • Eflornithine
  • Nifurtimox
  • Benznidazole
  • Metronidazole
  • Tinidazole
Prevention
  • Handwashing
  • Water treatment
  • Insecticide
  • Insect repellent
  • Protective clothing
  • Insecticides
  • Insect repellent
  • Bed nets
  • Protective clothing
  • Treatment of sex partners
  • Condoms

ELISA: enzyme-linked immunosorbent assay

DFA: direct immunofluorescence assay

NAAT: nucleic acid amplification assay

PCR: polymerase chain reaction

Differential Diagnosis

  • Histoplasmosis: a fungal infection that can present with skin lesions (nodules, ulcers, plaques). Histoplasmosis also spreads hematogenously to lymph nodes, liver, spleen, and bone marrow in immunocompromised patients. Pulmonary illness, though, is a more common manifestation. Urine and serum antigen assays, and culture with travel history can help differentiate the causative agent. 
  • Coccidioidomycosis: a fungal infection principally manifesting with pulmonary symptoms. Painful erythematous nodules also can occur. Blood count may show leukocytosis and eosinophilia. History and serologic testing point to the diagnosis.
  • Leprosy: a disease caused by Mycobacterium leprae, often presents with similar cutaneous manifestations that cause scarring and deformities. Leprosy affects the skin and peripheral nerves. So, leprosy often causes severe disfigurement with neuropathy, differentiating leprosy from leishmaniasis. 
  • Squamous cell carcinoma: central ulcerations may be confused with large squamous cell carcinoma. Biopsy and travel history are helpful in distinguishing the cutaneous lesions. 
  • Sporotrichosis: infection caused by Sporothrix schenckii. Lymphocutaneous infection is the most common form and presents like cutaneous nocardiosis (inoculation of soil through skin with erythematous, nodular lesion(s) along lymphatic channels). Culture of aspirated material helps distinguish the organisms.
  • Malaria: mosquito-borne infectious disease caused by single-celled micro-organisms of the Plasmodium group. Malaria presents with fever and chills in intervals, with anemia and splenomegaly among other findings that are similar to VL. History and peripheral blood smear (which identifies the infecting parasite) aid in diagnosis.

References

  1. Aronson, N. (2020). Cutaneous leishmaniasis: Clinical manifestation and diagnosis. UpToDate, Retrieved December 11, 2020, from https://www.uptodate.com/contents/cutaneous-leishmaniasis-clinical-manifestations-and-diagnosis
  2. Aronson, N. (2020). Cutaneous leishmaniasis: Treatment. UpToDate, Retrieved December 11, 2020, from https://www.uptodate.com/contents/cutaneous-leishmaniasis-treatment
  3. Bern, C. (2019). Visceral leishmaniasis: Epidemiology and control. UpToDate, Retrieved December 11, 2020, from https://www.uptodate.com/contents/visceral-leishmaniasis-epidemiology-and-control
  4. Bern, C. (2020). Visceral leishmaniasis: Treatment. UpToDate, Retrieved December 11, 2020, from https://www.uptodate.com/contents/visceral-leishmaniasis-treatment 
  5. Ryan, K.J.(Ed.), (2017). Sarcomastigophora the flagellates. Sherris Medical Microbiology, 7e. McGraw-Hill.
  6. Riedel, S., Jawetz, E., Melnick, J. L., & Adelberg, E. A. (2019). Jawetz, Melnick & Adelberg’s Medical microbiology (pp. 733-734). New York: McGraw-Hill Education.
  7. Sundar, S. (2018). Leishmaniasis. Jameson J, & Fauci A.S., & Kasper D.L., & Hauser S.L., & Longo D.L., & Loscalzo J (Eds.),  Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill. 
  8. Stark, C., & Vidyashankar, C. (2020) Leishmaniasis. Medscape. Retrieved 27 Dec 2020, from https://emedicine.medscape.com/article/220298-overview

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