Infectious Diseases

Trypanosoma African

OVERVIEW: What every clinician needs to know

Parasite name and classification

Human African trypanosomiasis (sleeping sickness) is caused by the protozoan parasites Trypanosoma brucei rhodesiense in East Africa, and Trypanosoma brucei gambiense in West and Central Africa.

What is the best treatment?

  • Pentamidine 4 mg/kg daily intramuscularly or intravenously is effective for T. b. gambiense unless there is central nervous system (CNS) disease.

    • It must be given intramuscularly (painful) or intravenously (not feasible in resource limited settings).

    • Adverse effects include nausea, hypotension, dizziness and pruritis, electrolyte abnormalities, ventricular arrhythmias, and renal failure.

  • Suramin 20 mg/kg intravenously on days 1, 3, 7, 14, and 21 is first-line treatment for T. b. rodesiense in early disease without CNS involvement, and is an alternative agent for T. b. gambiense.

    • Immediate hypersensitivity reactions can occur, so a test dose should be given.

    • Renal insufficiency and pancytopenia can also occur.

  • Melarsoprol is a trivalent arsenical compound that can be used in late stages of infection with T. b. gambiense and T. b. rhodesiense including CNS disease—the World Health Organization recommends an increasing dose schedule, but this may not be followed in practice.

    • 0.36 mg/kg day 1; 0.72 mg/kg day 2; 1.1 mg/kg day 3; 1.8 mg/kg days 10, 11, and 12; 2.2 mg/kg day 19; 2.9 mg/kg day 20; 3.6 mg/kg days 21, 28, 29, and 30 to maximum 180mg.

    • Melarsoprol can result in arsenic encephalopathy in up to 10% of treated patients and can be fatal.

    • It can also cause reactive encephalopathy in 10% of patients with 5% mortality, presumably related to destruction of trympanosomes in the CNS. This can be decreased by half with co-administered prednisolone.

  • Eflornithine 100 mg/kg IV q6h for 14 days can be used in late stage T. b. gambiense with CNS involvement. It is not effective against T. b. rhodesiense.

    • Its adverse effects include vomiting, seizures, bone marrow toxicity, arthralgias, and rash. However, it is better tolerated than melarsoprol.

  • Nifurtimox can be used in combination with other drugs in relapsed trypanosomiasis.

  • Nifurtimox and eflornithine combination therapy (NECT) had comparable efficacy to eflornithine monotherapy in one study, but decreased adverse events due to a lower overall dose of eflornithine. This is becoming the preferred regimen for last stage T. b. gambiense infection.

  • Further relapses after a course of each drug has been tried can be treated with NECT.

  • Relapses in late T. b. gambiense infection should be treated with eflornithine or melarsoprol (whichever was not used initially).

  • For patients with early T. b. rhodesiense infection, suramin is the first choice.

  • In late infection with T. b. rhodesiense, melarsoprol is the only option, eflornithine will not work.

  • Resistance to melarsoprol has been documented in T. b. rhodesiense.

What are the clinical manifestations of infection with these organisms?

  • Both T. b. gambiense and T. b. rhodesiense have an early stage with an initial inoculation site (chancre) followed by lymph node infection and parasitemia, and a late stage with CNS involvement.

  • The chancre is at the site of the initial bite and inoculation and occurs a week after the bite. It is a painful, red, papule 2cm to 4cm in diameter. It can resolve without specific treatment.

  • Trypanosomes then travel to lymph nodes, and lymphadenopathy is more commonly seen with T. b. gambiense.

  • In T. b. gambiense, early symptoms may develop gradually with intermittent fever, headaches, malaise, weight loss, and rash.

  • Occasionally symptoms will present years after exposure.

  • In late stage T. b. gambiense infection, headache, sensorineural disorders, personality changes, tremor, and frank psychosis can occur. Focal neurologic signs are usually absent. Disruption of the normal circadian rhythm cause daytime somnolence leading to the common name ‘sleeping sickness’. Patients become less arousable with progressive disease, leading to coma and death.

  • T. b. rhodesiense infection may have similar symptoms, but they occur much more rapidly. This is an acute febrile illness that rapidly worsens with CNS dysfunction over a few weeks.

  • Splenomegaly and lymphadenopathy may be seen in early disease, although this and other early manifestations are nonspecific.

  • The marked somnolence and eventual altered mental status that is the hallmark of sleeping sickness can be seen.

  • Cachexia can develop in T. b. gambiense infection since worsening is gradual and patients become too somnolent to eat.

Do other diseases mimic its manifestations?

  • Sleeping sickness should be differentiated from other conditions, such as human immunodeficiency virus infection, miliary tuberculosis, cerebral malaria, lymphoma, and connective tissue disease.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

  • Anemia can be seen, as well as thrombocytopenia and leukocytosis.

  • Hypoalbuminemia and hypergammaglobulinemia are also seen.

  • Cerebrospinal fluid (CSF) must be evaluated in all cases of suspected African trypanosomiasis in order to stage the infection for proper treatment.

  • White blood cell count greater than 5 and elevated protein are considered evidence of CNS disease, but are nonspecific.

  • Parasites are sometimes detectable in CSF, but their absence does not rule out CNS disease.

  • Mott cells are plasma cells that are occasionally seen in the CSF.

Results that confirm the diagnosis

  • Thick and thin Giemsa-stained blood smears may show trypanosomes. These are more likely to be positive in early infection when parasitemia precominates and in T. b. rhodesiense infection, which has higher levels of parasitemia overall.

  • Smears should be repeated on consecutive days to maximize yield, and there are concentration techniques (centrifugation, mini-anion exchange column) that can further increase sensitivity.

  • Aspiration of lymph nodes may show motile parasites on direct microscopy. This is commonly used in T. b. gambiense infection in which lymphadenopathy is pronounced.

  • Cultures of lymph nodes, CSF, blood, and bone marrow are done in liquid culture media.

  • Serology is available for T. b. gambiense, but still in development for T. b. rhodesiense.

  • The most commonly used test for serologic screening is the card agglutination test for trypanosomes (CATT) with a sensitivity of 94% and variable specificity.

  • Intrathecal levels of immunoglobulin M are the most sensitive indicator of CNS involvement.

  • Polymerase chain reaction assay is under study, but is not widely available in endemic countries.

  • Mass spectrometry is also being increasingly evaluated as a highly sensitive and specific diagnostic tool.

What imaging studies will be helpful in making or excluding the diagnosis of African trypanosomiasis?

  • Imaging studies are not routinely performed.

What complications can be associated with this parasitic infection, and are there additional treatments that can help to alleviate these complications?

Up to 5% mortality can be associated with treatments for African trypanosomiasis. Even with late disease, most adult patients who survive treatment do not have long term sequelae. Children can have neurological residua and motor delays.

What is the life cycle of the parasite, and how does the life cycle explain infection in humans? What is the epidemiology of this disease?

  • Parasite life cycle

    • A flagellated metacyclic trypomastigote is the form of the parasite that lives in the tsetse fly vector. When the fly bites an mammalian host, the parasites are transmitted and a chancre develops at the site of inoculation. The organisms then enter regional lymphatics and then the blood stream, where they change form into slender trypomastigotes that can be seen on blood smears.

    • The organism can cross the CSF barrier and enter the CNS.

    • When a tsetse fly takes a blood meal from an infected host, the trypomastigotes transform into procyclic trypomastigotes in the midgut and replicate. They then move to the salivary gland and again become metacyclic trypomastigotes.

    • A full diagram of the life cycle can be found on the US Centers for Disease Control and Prevention website. (Centers for Disease Control and Prevention. Parasites—African Trypanosomiasis (also known as Sleeping Sickness). Available at: http://www.cdc.gov/parasites/sleepingsickness/biology.html. Accessed 29 May 2012.)

    • The key vector is the tsetse fly, which occurs in sub-Saharan Africa. However, different vectors transmit T. b. gambiense (tsetse flies of the Glossina palpalis group) and T. b. rhodesiense (Glossina morsitans).

  • Epidemiology

    • There is not significant seasonal variation.

    • The tsestse flies of the Glossina palpalis group that transmit T. b. gambiense in West Africa live in humid conditions near rivers and preferentially feeds on humans.

    • The tsestse flies of the Glossina morsitans group that transmit T. b. rhodesiense in East Africa live in dry, open woodlands and preferentially bite wild antelope or deer and domestic cattle and goats.

    • Travelers on safari can become infected if bitten by an infected fly.

    • It is estimated that there are 300,000 to 500,000 people currently infected. The countries heavily affected include Congo, Sudan, and Angola (T. b. gambiense), Tanzania (T. b. rhodesiense) and Uganda (both).

    • Incidence is increasing, there is a current epidemic that began in 1970 and has been worsened by civil war, migration, economic collapse, and poor public health infrastructures.

  • Infection control issues

    • There is no need for isolation precautions.

    • There is no role for chemoprophylaxis.

    • There is no vaccine available for African trypanosomiasis.

    • Those going to endemic areas can use repellant, wear long pants and sleeves, and seek medical care early if symptoms develop after a bite.

    • Since tsetse flies are attracted to the color blue, fly traps are often this color. Insecticide treated screens are also used. In epidemics, spraying with insecticides or removal of the flies brush habitat can also assist in control. All of these efforts are difficult to sustain over time.

    • Case finding in humans seeks to reduce the reservoir of infection by treating people during the early, asymptomatic stage. This is only useful for T. b. gambiense, as it does not have significant animal reservoirs and has a more gradual clinical course than T. b. rhodesiense.

How do these organisms cause disease?

  • Trypanosomes present major variant surface glycoprotein. Antigenic variation of this protein allows the organism to evade immune clearance, and can result in ‘waves’ of parasitemia.

  • They can persist even in the presence of interferon-γ and are not easily cleared by complement.

  • Generalized suppression of humoral and cellular immune response is seen, yet there is also inflammation and immune complex deposition that may contribute to organ dysfunction.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Matovu, E, Kazibwe, AJ, Mugasa, CM, Ndungu, JM, Njiru, ZK. "Towards point-of-care diagnostic and staging tools for human African trypanosomiaisis". J Trop Med. vol. 2012. 2012. pp. 340538.

(This article outlines the current diagnostic tests and staging algorithms, and reviews the need for improving these tools in order to more rapidly diagnose cases and therefore reduce morbidity and mortality.)

Gobbi, F, Bisoffi, Z. "Human African trypanosomiasis in travellers to Kenya". Euro Surveill. 2012. pp. 17.

(Reviews sleeping sickness that occurs in returning travelers.)

La Greca, F, Magez, S. "Vaccination against trypanosomiasis: can it be done or is the trypanosome truly the ultimate immune destroyer and escape artist". Hum Vaccin. vol. 7. 2011. pp. 1225-33.

(A good summary of the challenges of trying to develop an anti-trypanosome vaccine.)

Rudenko, G. "African trypanosomes: the genome and adaptations for immune evasion". Essays Biochem. vol. 51. 2011. pp. 47-62.

(An overview of the basic immunology and pathogenesis of the typranosome.)

Simarro, PP, Franco, J, Diarra, A, Postigo, JA, Jannin, J. "Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis". Parasitology. vol. 6. 2012. pp. 1-5.

(An excellent and thoughtful exporation of the limitations of current available treatments, the importance of treatment costs in developing countries, and potential new treatments for African trypanosomiasis.)

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