Trypanosoma brucei/African trypanosomiasis

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)

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)

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

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

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

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

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.