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”)
- Cutaneous leishmaniasis (CL), also called:
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
- Old World leishmaniasis:
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.
- Bite of an infected sandfly (vector):
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
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.
Related videos
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).
- Localized CL:
Skin ulcer due to leishmaniasis noted on the hand of an adult from Central America
Image: “Skin ulcer due to leishmaniasis” by CDC/ Dr. D.S. Martin. License: Public DomainDiffuse or disseminated CL: seen in a patient with human immunodeficiency syndrome (HIV)
Image: “Diffuse or disseminated cutaneous leishmaniasis” by Rotterdam Centre for Tropical Medicine, Rotterdam, The Netherlands. License: CC BY 4.0Cutaneous leishmaniasis: leishmaniasis ulcer on left forearm
Image: “Leishmaniasis ulcer on left forearm” by Layne Harris. License: Public Domain
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
- Histopathologic examination of the specimen:
Visceral leishmaniasis: bone marrow slide showing Leishman-Donovan bodies (arrow)
Image: “Leishman-Donovan bodies” by Department of Medicine, Maulana Azad Medical College, Bahadur Shah Zafar Marg, New Delhi, 110002, India. License: CC BY 2.0Cutaneous leishmaniasis
Image: “Wright’s and Leishmann’s stains” by Hafizur Rahman et al. License: CC BY 2.5
2A: dermal skin scrapings in Wright’s stain showing Leishman-Donovan bodies (amastigotes) in the macrophage
2B: dermal skin scrapings in Leishman’s stain
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
Giardia | Leishmania | Trypanosoma | Trichomonas | |
---|---|---|---|---|
Characteristics |
|
|
|
|
Forms |
|
|
|
|
Transmission |
|
|
| Sexually transmitted |
Clinical | Giardiasis | Leishmaniasis |
| Trichomoniasis |
Diagnosis |
|
|
|
|
Treatment |
| Depends on the clinical syndrome:
| Depends on the clinical disease:
|
|
Prevention |
|
|
|
|
ELISA: enzyme-linked immunosorbent assay
DFA: direct immunofluorescence assay
NAAT: nucleic acid amplification assay
PCR: polymerase chain reaction
Blood smear demonstrating Trypanosoma trypomastigotes
Image: “Ms. Michaels forms” by CDC/Dr. Myron G. Schultz. License: Public DomainGiemsa’s stain of Giardia lamblia trophozoites
Image: “Trophozoites of Giardia lamblia” by Eva Nohýnková, Department of Tropical Medicine, 1st Faculty of Medicine, Charles University in Prague and Hospital Bulovka, Czech Republic. License: CC BY 4.0Giemsa’s stain of Leishmania promastigotes
Image: “Giemsa stain” by Arriyadh Community College, King Saud University, P.O. Box 28095, Riyadh 11437, Saudi Arabia. License: CC BY 3.0Microscopic images of Trichomonas vaginalis trophozoites
Image: “Trichomonas protozoa” by isis325. License: CC BY 2.0.
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
- 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
- Aronson, N. (2020). Cutaneous leishmaniasis: Treatment. UpToDate, Retrieved December 11, 2020, from https://www.uptodate.com/contents/cutaneous-leishmaniasis-treatment
- Bern, C. (2019). Visceral leishmaniasis: Epidemiology and control. UpToDate, Retrieved December 11, 2020, from https://www.uptodate.com/contents/visceral-leishmaniasis-epidemiology-and-control
- Bern, C. (2020). Visceral leishmaniasis: Treatment. UpToDate, Retrieved December 11, 2020, from https://www.uptodate.com/contents/visceral-leishmaniasis-treatment
- Ryan, K.J.(Ed.), (2017). Sarcomastigophora the flagellates. Sherris Medical Microbiology, 7e. McGraw-Hill.
- 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.
- 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.
- Stark, C., & Vidyashankar, C. (2020) Leishmaniasis. Medscape. Retrieved 27 Dec 2020, from https://emedicine.medscape.com/article/220298-overview