Leishmaniasis

Leishmaniasis is a parasitic disease caused by protozoans of the Leishmania genus, which are transmitted by infected phlebotomine sandflies. Depending on the parasite subtype and the strength of the host's immune system, the infection may be asymptomatic or manifest in a cutaneous, mucosal, or visceral form. Cutaneous leishmaniasis is characterized by skin ulcers. The most severe clinical form of visceral leishmaniasis is kala-azar (Hindi for “black fever”), characterized by fever, weight loss, hepatosplenomegaly, and immunosuppression. Leishmaniasis is diagnosed by microscopic visualization of macrophages containing amastigotes from skin or other tissue specimens. Simple cases of cutaneous leishmaniasis in immunocompetent patients may be observed for clinical resolution. Local treatment (cryotherapy, topical paromomycin) suffices for most other cases of cutaneous leishmaniasis. Visceral leishmaniasis requires systemic treatment, e.g., with liposomal amphotericin B.

• Distribution: endemic in the Mediterranean region, Africa, India, southwest and central Asia, South and Central America ^[1][2]
• Global incidence
  • Visceral: 50,000– 90,000 infections/year ^[3]
  • Cutaneous: 600,000–1,000,000 infections/year ^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Pathogen: Leishmania species (protozoan) ^[4][5]
  • Cutaneous leishmaniasis
    • Americas (i.e., New World): L. mexicana, subgenus Viannia (e.g., L. braziliensis, L. guyanensis, L. panamensis), which can also cause mucosal leishmaniasis
    • Asia/Africa (i.e., Old World): L. major, L. tropica. L. aethiopica, L. infantum, L. donovani
  • Visceral leishmaniasis: L. donovani, L. infantum
• Transmission
  • Vector: phlebotomine sand fly
  • Reservoir: mammals (especially dogs, humans, and rodents)

Clinical features ^[1][4]

Approx. 10% of infections are asymptomatic. ^[1]

• Localized cutaneous leishmaniasis
  • Incubation period: weeks to months ^[5]
  • Manifestations
    • Painless solitary or multiple reddish macules and/or papules around the sandfly bite that increase in size and develop central ulceration
    • Regional lymphadenopathy
    • Nodular lymphangitis
    • Spontaneous healing over months to years
    • Atrophic scars
• Mucosal leishmaniasis
  • Onset: months to years after untreated or improperly treated cutaneous leishmaniasis ^[1]
  • Manifestations ^[5]
    • Sores and/or destructive mucosal lesions
    • Nasopharynx (common): mucosal bleeding, nasal blockage and/or congestion, coryza, hyposmia, tissue or scab expulsion
    • Oral, pharyngeal, or laryngeal: dysphagia, odynophagia, brassy cough, hoarseness, bleeding, pain
• Other manifestations: Diffuse or disseminated may be seen in immunocompromised individuals. ^[6]
  • Diffuse cutaneous leishmaniasis: multiple diffuse, non-ulcerating, painless papules and nodules
  • Disseminated cutaneous leishmaniasis: ≥ 10 mixed-type lesions on ≥ 2 parts of the body
  • Leishmania recidivans: new lesions developing around an old scar from cutaneous leishmaniasis from L. tropica

Mucosal leishmaniasis can develop in individuals infected with species in the Viannia subgenus (e.g., L. [V.] braziliensis, L. [V.] panamensis, L. [V.] guyanensis). ^[5]

Diagnostics ^[1][4]

Consider cutaneous leishmaniasis in individuals with nonhealing skin lesions who have been in endemic regions.

• Clinical evaluation
  • Detailed travel and exposure history
  • Detailed examination of the skin and mucus membranes
  • Referral for laryngoscopy if mucosal involvement is suspected
• Direct detection
  • Indication: all patients with suspected cutaneous or mucosal leishmaniasis
  • Specimen: tissue sample (e.g., via biopsy, aspirate, scraping, or brushing) of a cleaned, active lesion
  • Methods: Obtain all of the following studies to maximize diagnostic yield.
    • Microscopy: macrophages that contain amastigotes on histopathology of tissue section ^[6]
    • Tissue culture: Novy-MacNeal-Nicolle medium ^[7]
    • Molecular testing: PCR

Treatment

The objective of treatment is to manage clinical symptoms.

General Principles ^[4]

• Consult an infectious disease or tropical medicine specialist for guidance.
• Treatment depends on the extent of the disease.
  • Expectant management in immunocompetent patients with simple disease, e.g.:
    • ≤ 4 small (< 1 cm) healing lesions in nonexposed skin regions
    • No presence of or risk for mucosal disease (e.g., infection acquired in the Americas)
  • Local or systemic therapy in all other cases
• Wound care for ulcerated lesions (see also “follow-up for open wounds”)
• Admit patients with laryngeal or pharyngeal disease.
• Monitor for 6–12 months for adequate healing and/or treatment response.

Patients may experience a paradoxical increase in the local inflammatory response during the first 2–3 weeks of treatment.

Local therapy ^[4]

• Indications: skin lesions that don't spontaneously heal in simple disease
• Options
  • Cryotherapy or thermotherapy
  • Topical paromomycin

Systemic therapy ^[4]

• Indications
  • Complex disease, e.g., patients with:
    • Large or numerous lesions
    • Immunocompromise
    • Presence or risk of mucosal disease
    • Lesions on exposed skin or genitalia
  • Less common syndromes (i.e., leishmaniasis recividans, diffuse or disseminated leishmaniasis)
• Options: Similar to visceral leishmaniasis; choice of therapy should be individualized.
  • Oral: miltefosine, azoles (e.g., ketoconazole, fluconazole)
  • Parenteral: pentavalent antimonial (e.g., sodium stibogluconate ), amphotericin B, pentamidine

Prognosis

Treatment reduces the recurrence rate of cutaneous leishmaniasis, accelerates the healing of lesions, and reduces the risk of dissemination and incidence of mucosal leishmaniasis.

Without treatment, localized cutaneous leishmaniasis resolves over months to years, resulting in atrophic scars or keloids. Reactivation may occur years after initial symptoms resolve.

Clinical features ^[5]

• Incubation period: 2 weeks to 8 months ^[6]
• Many patients are asymptomatic.
• Kala-azar (Hindi for “black fever,” in reference to the darkening of the skin it can cause)
  • Usually insidious progression
  • Flu-like symptoms, spiking fevers
  • Weight loss
  • Lymphadenopathy
  • Hepatosplenomegaly
  • Ascites and edema
  • Possible darkened or gray skin (especially on the palms and soles)

Diagnostics ^[4][5]

Routine laboratory studies

• CBC: pancytopenia ^[8]
  • Hemolytic anemia
  • Neutropenia, eosinopenia
  • Thrombocytopenia
• Liver chemistries
  • ↑ Transaminases
  • ↓ Albumin
  • ↑ Total protein
• Inflammatory markers: ↑ ESR ^[8]
• SPEP: hypergammaglobulinemia
• HIV test ^[6]
• Additional testing in immunocompromised individuals
  • Blood cultures
  • Serum PCR for Leishmania

Diagnostic confirmation

Definitive diagnosis of visceral leishmaniasis requires tissue aspiration or biopsy.

• Tissue aspirate or biopsy
  • Indication: all patients with suspected visceral leishmaniasis
  • Specimen: bone marrow (preferred), liver, lymph node
  • Methods: Obtain all of the following studies to maximize diagnostic yield.
    • Microscopy: macrophages with amastigotes on histopathology of tissue section
    • Culture
    • Molecular testing: PCR
• Serologic testing: supports the diagnosis if positive (may be falsely negative in immunocompromised patients)

Treatment ^[4][5]

General principles ^[4]

• Consult an infectious disease or tropical medicine specialist for guidance.
• All patients with clinical and laboratory findings of visceral leishmaniasis should receive systemic therapy.
• Monitor all patients clinically for up to one year.

Systemic therapy ^[5]

• Preferred: : Liposomal Amphotericin B on days 1–5, 14, and 21 for immunocompetent patients ^[5]
• Alternatives
  • Miltefosine
  • Pentavalent antimonial (e.g., sodium stibogluconate)
  • Pentamidine
  • Paromomycin ^[5]

Kala-azar is highly fatal without treatment.

Patients with immunosuppression are treated with a higher dose for a longer duration.

Complications ^[2][6]

• Post-kala-azar dermal leishmaniasis
  • A late complication of treated visceral leishmaniasis characterized by the formation of dermal lesions containing amastigotes
  • Clinical features
    • Dermal hypopigmented nodules, papules, and/or macules
    • Lesions start on the face and then spread to the torso and extremities
  • Treatment (i.e., conservative management or prolonged systemic therapy) is determined by the location of infection acquisition. ^[6]
• Hemophagocytic lymphohistiocytosis: Severe pancytopenia with inflammation may develop. ^[8]
• Secondary bacterial infections: e.g., pneumonia, acute otitis media, sepsis, skin and soft tissue infections