Trypanosoma brucei/African trypanosomiasis

African trypanosomiasis, or African sleeping sickness, is a parasitic infection caused by the protozoa Trypanosoma brucei. There are 2 notable subtypes, T. brucei gambiense and T. brucei rhodesiense. Transmission is primarily vector borne through the tsetse fly. Initial infections present with localized inflammation (chancre), cervical lymphadenopathy, intermittent fevers, and other nonspecific findings. If untreated, CNS involvement occurs, which is characterized by sleep disturbances, behavioral changes, coma, and death. Diagnosis is confirmed by the identification of trypanosomes on blood smear or serology. Treatment is dependent on the subtype and stage of the disease. Early treatment and prevention are key in preventing long-term sequelae and death.

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General Characteristics and Epidemiology

General features of Trypanosoma brucei

  • Parasitic protozoan 
  • Taxonomy:
    • Family: Trypanosomatidae
    • Genus: Trypanosoma
    • Subspecies: 
      • T. brucei gambiense 
      • T. brucei rhodesiense
  • General characteristics: 
    • Single flagellum
    • Undulating membrane
    • Variable surface glycoproteins allow for antigenic variation.
  • Morphologic forms:
    • Epimastigote (noninfectious form)
    • Trypomastigotes (infectious form)
Trypanosomes in a Giemsa-stained thin blood film

Trypanosomes in a Giemsa-stained thin blood film from a traveler returning from Tanzania

Image: “Trypanosomes in a Giemsa-stained thin blood film from a Spanish traveler returning from Tanzania” by Joan Gómez-Junyent et al. License: CC BY 4.0

Associated diseases

T. brucei causes African trypanosomiasis, also known as African sleeping sickness.

Epidemiology

  • Geographic distribution:
    • Western and Central Africa (gambiense subtype)
    • Eastern and Southern Africa (rhodesience subtype)
  • Incidence: 
    • 933 new cases reported in 2018 (> 98% were the gambiense subtype)
    • < 1 case per year in the US (in travelers)
Geographic distribution of African trypanosomiasis

Geographic distribution of African trypanosomiasis: T. brucei is only found in the blue areas.

Image: “T. brucei is only found in the blue areas” by Beck, H.E. et al. License: CC BY 4.0

Pathogenesis

Reservoir

  • T. b. rhodesiense: wild game animals and cattle
  • T. b. gambiense: primarily humans

Transmission

  • Primarily vector-borne transmission: tsetse fly
  • Less common:
    • Blood transfusion
    • Organ transplantation
    • Laboratory inoculation
    • Congenital infections

Host risk factors

  • Residence in endemic regions
  • Prolonged exposure to vectors

Life cycle and pathophysiology

  • Tsetse fly feeds on an infected human or mammal host → becomes infected with trypomastigotes (infectious form)
    • Trypomastigotes migrate to midgut of the tsetse fly → replicate (binary fission)
    • Migrate to salivary gland → differentiate into epimastigotes (noninfectious form)
    • After approximately 3 weeks, differentiate into trypomastigotes 
  • Infected tsetse fly bites host → injects trypomastigotes into host tissue → chancre develops, secondary to localized inflammation
  • Trypomastigotes migrate to regional lymphatics → disseminate through the bloodstream
  • Motility of trypomastigotes allows invasion of the surrounding connective tissues, including CSF and CNS.
  • Disease progression is dependent on subspecies:
    • Rhodesiense: incubation period of weeks
    • Gambiense: incubation period of months to years
pathogenesis of African trypanosomiasis

Image illustrating the pathogenesis of African trypanosomiasis

Image by Lecturio. License: CC BY-NC-SA 4.0

Clinical Presentation

African trypanosomiasis has 2 stages: the hemolymphatic stage and the neurologic stage

Stage 1: hemolymphatic phase

  • Localized symptoms:
    • Painful chance at the site of inoculation
      • Erythema
      • Induration
      • Variable appearance
      • Resolves spontaneously
    • Winterbottom sign: 
      • Painless lymphadenopathy of posterior cervical lymph nodes
      • Characteristic of T. b. gambiense infections
  • Nonspecific systemic symptoms:
    • Intermittent fever
    • Headache
    • Malaise
    • Arthralgias
  • Less common symptoms:
    • Facial swelling
    • Hepatosplenomegaly
    • Generalized lymphadenopathy
    • Cardiomyopathy
    • Pruritic, erythematous rash
Cutaneous manifestations of African trypanosomiasis

Cutaneous manifestations of African trypanosomiasis:
A: a fine, pink rash on the abdomen
B: trypanosomal chancre on the patient’s left arm that occurs at the site of inoculation

Image: “Typical clinical manifestations of acute African trypanosomiasis imported from Uganda” by Paul M et al. License: CC BY 2.0

Stage 2: neurologic phase (meningoencephalitis)

  • Headache:
    • Persistent
    • Refractory to analgesics
  • Lymphadenopathy
  • Behavioral changes:
    • Personality changes
    • Confusion (difficulty concentrating and completing tasks)
    • Sensory disorders
    • Apathy
    • Psychosis
  • Neurologic symptoms:
    • Ataxia
    • Sensory disorders
    • Tremors
  • Sleep disorder: 
    • Daytime somnolence
    • Nighttime insomnia
    • Severe enough to cause anorexia, wasting, and malnutrition
  • Progression to coma and death, if untreated
time course of the African trypanosomiasis disease

Image showing the time course of African trypanosomiasis from initial infection to chronic illness months to years later (depending on the subspecies involved)

Image by Lecturio. License: CC BY-NC-SA 4.0

Diagnosis and Management

Diagnosis

  • Confirmatory tests:
    • Presence of trypomastigotes
      • Blood smear (thick or thin)
      • Chancre tissue aspirate
      • Lymph node biopsy
      • CSF analysis
    • Serologic testing: 
      • Card agglutination test for trypanosomiasis (CATT)
      • ELISA
      • PCR
  • Supportive findings:
    • Hemolytic anemia
    • Leukocytosis
    • Thrombocytopenia
    • ↑ Inflammatory markers (erythrocyte sedimentation rate and CRP)

Management

  • Rhodesiense subspecies: 
    • Stage 1: suramin
    • Stage 2: melarsoprol 
  • Gambiense subspecies: 
    • Stage 1: pentamidine
    • Stage 2: niturtimox and eflornithine

Prevention

  • No vaccine or prophylactic treatment is available.
  • Vector control with insecticides and insect repellants
  • Wear long sleeves and pants, and use neutral-colored clothing

Comparison of Flagellated Protozoa

Table: Comparison of clinically relevant flagellated protozoa
ProtozoaGiardiaLeishmaniaTrypanosomaTrichomonas
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
  • Undualting membrane
  • Ovoid shape
  • Facultative anaerobe
Forms
  • Cyst
  • Trophozoite
  • Promastigote
  • Amastigote
  • Trypomastigote
  • Amastigote
  • Epimastigote
  • Trophozoite
  • No cyst form
Transmission
  • Waterborne
  • Fecal-oral route
  • Vector (sandfly)
  • Human-to-human transmission
  • Zoonotic (rodents, dogs, foxes)
  • Vector (tsetse fly, kissing bug)
  • Blood transfusion
  • Sexually transmitted
Clinical
  • Giardiasis
  • Leishmaniasis
  • 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
  • Insecticides
  • Insect repellents
  • Protective clothing
  • Insecticides
  • Insect repellents
  • Bed nets
  • Protective clothing
  • Treatment of sexual partners
  • Use of condoms

DFA: direct immunofluorescence assay
NAAT: nucleic acid amplification test

Differential Diagnosis

  • Chagas disease: an infection caused by the American trypanosome, T. cruzi. Acute infections may present with inflammation at the inoculation site (chagoma), fever, and lymphadenopathy. Untreated chronic infections can progress to severe complications, including megacolon, megaesophagus, and cardiomyopathy. The diagnosis can be confirmed using blood smear, serology, or PCR. Treatment with benznidazole or nifurtimox is effective only in the acute phase.
  • Bacterial or fungal meningitis: Symptoms of bacterial meningitis may mimic those of the 2nd phase of sleeping sickness, including fever, headache, confusion, and myalgias. Diagnosis is confirmed by CSF analysis and/or serologic testing. Specific bacterial causes of meningitis vary depending on age group and risk factors. 
  • Malaria: a mosquito-borne infectious disease caused by Plasmodium species. Malaria often presents with fever, rigors, diaphoresis, jaundice, abdominal pain, hemolytic anemia, hepatosplenomegaly, and renal impairment. A blood smear shows a single pleomorphic ring. Rapid testing for Plasmodium antigens can also be performed. Management requires a prolonged course of multiple antimalarial drugs.
  • Psychiatric illness: Due to late-stage behavioral manifestations, sleeping sickness may be misdiagnosed as a psychiatric illness, especially in immigrants to nonendemic areas. It is important to evaluate for possible epidemiological exposure to prevent this misdiagnosis.

References

  1. Riedel, S., Jawetz, E., Melnick, J.L., Adelberg, E.A. (2019). Jawetz, Melnick & Adelberg’s Medical Microbiology, pp. 722-733 and 730-732. New York: McGraw-Hill Education.
  2. Krishna, S., Lindner, A., Lejon, V. (2021). Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis. UpToDate, Retrieved May 08, 2021, from https://www.uptodate.com/contents/human-african-trypanosomiasis-epidemiology-clinical-manifestations-and-diagnosis 
  3. Krishna, S., Lindner, A., Lejon, V. (2021). Human African trypanosomiasis: Treatment and prevention. UpToDate, Retrieved May 08, 2021, from https://www.uptodate.com/contents/human-african-trypanosomiasis-treatment-and-prevention
  4. Pearson, R.D. (2020). African trypanosomiasis (African sleeping sickness). MSD Manual Professional Version. Retrieved June 13, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/extraintestinal-protozoa/african-trypanosomiasis
  5. Dunn, N., Wang, S., and Adigun, R. (2021). African trypanosomiasis. StatPearls. Retrieved June 13, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK519580/
  6. Hnaide, H.A. (2019). African trypanosomiasis (sleeping sickness). In Chandrasekar, P.H. (Ed.), Medscape. Retrieved June 13, 2021, from https://emedicine.medscape.com/article/228613-overview
  7. Centers for Disease Control and Prevention. (2020). Parasites – African trypanosomiasis (also known as sleeping sickness). Retrieved June 13, 2021, from https://www.cdc.gov/parasites/sleepingsickness/

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