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 Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation (chancre), cervical lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, intermittent fevers, and other nonspecific findings. If untreated, CNS involvement occurs, which is characterized by sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disturbances, behavioral changes, coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. 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 Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 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 Organ Transplantation Transplantation is a procedure that involves the removal of an organ or living tissue and placing it into a different part of the body or into a different person. Organ transplantations have become the therapeutic option of choice for many individuals with end-stage organ failure. 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 Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. 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 chancre at the site of inoculation
      • Erythema
      • Induration
      • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables appearance
      • Resolves spontaneously
    • Winterbottom sign: 
      • Painless lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy of posterior cervical lymph nodes
      • Characteristic of T. b. gambiense infections
  • Nonspecific systemic symptoms:
    • Intermittent fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Headache
    • Malaise
    • Arthralgias
  • Less common symptoms:
    • Facial swelling
    • Hepatosplenomegaly
    • Generalized lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
    • Cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies
    • 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 Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). 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 Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
    • Severe enough to cause anorexia, wasting, and malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries
  • Progression to coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. 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 Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia
    • Leukocytosis
    • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. 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 Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination 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
Protozoa Giardia Leishmania Leishmania 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. Leishmania/Leishmaniasis Trypanosoma Trichomonas
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 Giardiasis Giardiasis is caused by Giardia lamblia (G. lamblia), a flagellated protozoan that can infect the intestinal tract. The hallmark symptom of giardiasis is foul-smelling steatorrhea. Patients who develop chronic infections may experience weight loss, failure to thrive, and vitamin deficiencies as a result of malabsorption. Giardia/Giardiasis
  • Leishmaniasis Leishmaniasis Leishmania species are obligate intracellular parasites that are transmitted by an infected sandfly. 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. Leishmania/Leishmaniasis
  • African sleeping sickness
  • Chagas disease Chagas disease Chagas disease is an infection caused by the American trypanosome Trypanosoma cruzi. This parasitic protozoan is transmitted in the feces of reduviid bugs in South and Central America. Acute infection may present with inflammation at the inoculation site (chagoma), fever, and lymphadenopathy. Untreated, chronic infection can progress to severe complications. Trypanosoma cruzi/Chagas disease
  • Trichomoniasis
Diagnosis
  • ELISA
  • DFA
  • NAAT
  • Stool microscopy
  • Blood smear
  • Biopsy
  • PCR
  • Leishmanin skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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
  • Niturtimox
  • 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 Chagas disease Chagas disease is an infection caused by the American trypanosome Trypanosoma cruzi. This parasitic protozoan is transmitted in the feces of reduviid bugs in South and Central America. Acute infection may present with inflammation at the inoculation site (chagoma), fever, and lymphadenopathy. Untreated, chronic infection can progress to severe complications. Trypanosoma cruzi/Chagas disease: an infection caused by the American trypanosome, T. cruzi. Acute infections may present with inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation at the inoculation site (chagoma), fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy. Untreated chronic infections can progress to severe complications, including megacolon Megacolon Megacolon is a severe, abnormal dilatation of the colon, and is classified as acute or chronic. There are many etiologies of megacolon, including neuropathic and dysmotility conditions, severe infections, ischemia, and inflammatory bowel disease. 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 Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis: Symptoms of bacterial meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis may mimic those of the 2nd phase of sleeping sickness, including fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, confusion, and myalgias. Diagnosis is confirmed by CSF analysis and/or serologic testing. Specific bacterial causes of meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis vary depending on age group and risk factors. 
  • Malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Malaria: a mosquito-borne infectious disease caused by Plasmodium species. Malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Malaria often presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, rigors, diaphoresis, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of 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 Antimalarial drugs Malaria, a vector-borne parasitic disease caused by Plasmodium spp., is transmitted via injection of sporozoites or immature forms of the parasite into a person's bloodstream. Sporozoites then infect the hepatocytes and differentiate into schizonts, which subsequently rupture, and merozoites invade red blood cells. 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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