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 Surface glycoproteins Glycoproteins found on the membrane or surface of cells. Human Herpesvirus 8 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 Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency:
  • 933 new cases reported in 2018 (> 98% were the gambiense subtype)
  • < 1 case per year in the US (in travelers)

Pathogenesis

Reservoir Reservoir Animate or inanimate sources which normally harbor disease-causing organisms and thus serve as potential sources of disease outbreaks. Reservoirs are distinguished from vectors (disease vectors) and carriers, which are agents of disease transmission rather than continuing sources of potential disease outbreaks. Humans may serve both as disease reservoirs and carriers. Escherichia coli

• T. b. rhodesiense: wild game animals Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, animalia was one of the kingdoms. Under the modern three domain model, animalia represents one of the many groups in the domain eukaryota. Cell Types: Eukaryotic versus Prokaryotic and cattle
• T. b. gambiense: primarily humans

Transmission

• Primarily vector-borne Vector-Borne Antimalarial Drugs 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease

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 Midgut Development of the Abdominal Organs of the tsetse fly → replicate ( binary fission Binary fission Cell Types: Eukaryotic versus Prokaryotic)
  • Migrate to salivary gland Salivary gland Glands that secrete saliva in the mouth. There are three pairs of salivary glands (parotid gland; sublingual gland; submandibular gland). Diseases of the Salivary Glands → differentiate into epimastigotes (noninfectious form)
  • After approximately 3 weeks, differentiate into trypomastigotes 
• Infected tsetse fly bites host → injects trypomastigotes into host tissue → chancre Chancre The primary sore of syphilis, a painless indurated, eroded papule, occurring at the site of entry of the infection. Syphilis 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 Motility The motor activity of the gastrointestinal tract. Gastrointestinal Motility of trypomastigotes allows invasion of the surrounding connective tissues, including CSF and CNS.
• Disease progression is dependent on subspecies:
  • Rhodesiense: incubation Incubation The amount time between exposure to an infectious agent and becoming symptomatic. Rabies Virus period of weeks
  • Gambiense: incubation Incubation The amount time between exposure to an infectious agent and becoming symptomatic. Rabies Virus 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 Chancre The primary sore of syphilis, a painless indurated, eroded papule, occurring at the site of entry of the infection. Syphilis at the site of inoculation
    • Erythema Erythema Redness of the skin produced by congestion of the capillaries. This condition may result from a variety of disease processes. Chalazion
    • Induration Induration Dermatologic Examination
    • 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 Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy
    • Characteristic of T. b. gambiense infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
• Nonspecific systemic symptoms:
  • Intermittent fever Intermittent Fever Fever
  • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
  • Malaise Malaise Tick-borne Encephalitis Virus
  • Arthralgias
• Less common symptoms:
  • Facial swelling Swelling Inflammation
  • Hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus
  • Generalized lymphadenopathy Generalized Lymphadenopathy 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). Cardiomyopathy: Overview and Types
  • Pruritic, erythematous rash Rash Rocky Mountain Spotted Fever

Stage 2: neurologic phase Neurologic phase Tick-borne Encephalitis Virus ( meningoencephalitis Meningoencephalitis Encephalitis)

• Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess:
  • Persistent
  • Refractory to analgesics
• 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
• Behavioral changes:
  • Personality changes
  • Confusion (difficulty concentrating and completing tasks)
  • Sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology disorders
  • Apathy Apathy Lack of emotion or emotional expression; a disorder of motivation that persists over time. Wernicke Encephalopathy and Korsakoff Syndrome
  • Psychosis
• Neurologic symptoms:
  • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
  • Sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology disorders
  • Tremors
• Sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of 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 Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa, 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 Blood smear Myeloperoxidase Deficiency (thick or thin)
    • Chancre Chancre The primary sore of syphilis, a painless indurated, eroded papule, occurring at the site of entry of the infection. Syphilis tissue aspirate
    • Lymph node biopsy Lymph Node Biopsy Lymphadenopathy
    • CSF analysis CSF analysis Meningitis
  • Serologic testing:
    • Card agglutination test for trypanosomiasis (CATT)
    • ELISA ELISA An immunoassay utilizing an antibody labeled with an enzyme marker such as horseradish peroxidase. While either the enzyme or the antibody is bound to an immunosorbent substrate, they both retain their biologic activity; the change in enzyme activity as a result of the enzyme-antibody-antigen reaction is proportional to the concentration of the antigen and can be measured spectrophotometrically or with the naked eye. Many variations of the method have been developed. St. Louis Encephalitis Virus
    • PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (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 Leukocytosis A transient increase in the number of leukocytes in a body fluid. West Nile Virus
  • 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 Erythrocyte Sedimentation Rate Soft Tissue Abscess 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 Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination or prophylactic treatment is available.
• Vector control with insecticides Insecticides Pesticides designed to control insects that are harmful to man. The insects may be directly harmful, as those acting as disease vectors, or indirectly harmful, as destroyers of crops, food products, or textile fabrics. Trypanosoma cruzi/Chagas disease and insect repellants
• Wear long sleeves and pants, and use neutral-colored clothing

Comparison of Flagellated Protozoa

Differential Diagnosis

• Chagas disease Chagas disease Infection with the protozoan parasite trypanosoma cruzi, a form of trypanosomiasis endemic in central and south america. It is named after the brazilian physician carlos chagas, who discovered the parasite. Infection by the parasite (positive serologic result only) is distinguished from the clinical manifestations that develop years later, such as destruction of parasympathetic ganglia; chagas cardiomyopathy; and dysfunction of the esophagus or colon. Trypanosoma cruzi/Chagas disease: an infection caused by the American trypanosome, T. cruzi. Acute infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 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 Inoculation site Yellow Fever Virus ( chagoma Chagoma Trypanosoma cruzi/Chagas disease), 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 Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 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 Megaesophagus Trypanosoma cruzi/Chagas disease, and 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). Cardiomyopathy: Overview and Types. The diagnosis can be confirmed using blood smear Blood smear Myeloperoxidase Deficiency, serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus, or PCR PCR Polymerase chain reaction (PCR) is a technique that amplifies DNA fragments exponentially for analysis. The process is highly specific, allowing for the targeting of specific genomic sequences, even with minuscule sample amounts. The PCR cycles multiple times through 3 phases: denaturation of the template DNA, annealing of a specific primer to the individual DNA strands, and synthesis/elongation of new DNA molecules. Polymerase Chain Reaction (PCR). Treatment with benznidazole Benznidazole Trypanosoma cruzi/Chagas disease or nifurtimox Nifurtimox A nitrofuran thiazine that has been used against trypanosomiasis. Trypanosoma cruzi/Chagas disease is effective only in the acute phase Acute phase Short Bowel Syndrome.
• Bacterial or fungal meningitis Fungal meningitis Meningitis caused by fungal agents which may occur as opportunistic infections or arise in immunocompetent hosts. Meningitis: Symptoms of bacterial meningitis Bacterial meningitis Bacterial infections of the leptomeninges and subarachnoid space, frequently involving the cerebral cortex, cranial nerves, cerebral blood vessels, spinal cord, and nerve roots. 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 Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, confusion, and myalgias Myalgias Painful sensation in the muscles. Tick-borne Encephalitis Virus. Diagnosis is confirmed by CSF analysis CSF analysis Meningitis 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. Plasmodium/Malaria: a mosquito-borne infectious disease caused by Plasmodium Plasmodium A genus of protozoa that comprise the malaria parasites of mammals. Four species infect humans (although occasional infections with primate malarias may occur). These are plasmodium falciparum; plasmodium malariae; plasmodium ovale, and plasmodium vivax. Species causing infection in vertebrates other than man include: plasmodium berghei; plasmodium chabaudi; p. Vinckei, and plasmodium yoelii in rodents; p. Brasilianum, plasmodium cynomolgi; and plasmodium knowlesi in monkeys; and plasmodium gallinaceum in chickens. Antimalarial Drugs 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. Plasmodium/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 Rigors Fever, 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 Abdominal Pain Acute Abdomen, 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, hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, and renal impairment. A blood smear Blood smear Myeloperoxidase Deficiency shows a single pleomorphic Pleomorphic Bacteroides ring. Rapid testing for Plasmodium Plasmodium A genus of protozoa that comprise the malaria parasites of mammals. Four species infect humans (although occasional infections with primate malarias may occur). These are plasmodium falciparum; plasmodium malariae; plasmodium ovale, and plasmodium vivax. Species causing infection in vertebrates other than man include: plasmodium berghei; plasmodium chabaudi; p. Vinckei, and plasmodium yoelii in rodents; p. Brasilianum, plasmodium cynomolgi; and plasmodium knowlesi in monkeys; and plasmodium gallinaceum in chickens. Antimalarial Drugs 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.