African Trypanosomiasis

African Sleeping Sickness

 

 

Introduction        Pathogenesis        Diagnosis        Treatment        Vector        Epidemiology        Prevention

     History of Discovery         Morphology                                                                                                                   Transmission Trends

         Life Cycle                                                                                                                      Disease in Animals                 

                     VSG

                     Clinical Presentation

 

 

 

 

 

A group of young boys attend a funeral in the Ivory Coast for

a woman believed to have died from African sleeping sickness.[1]

                       

Introduction

 

“From the beginning of Arab and European influence in the hinterland of tropical Africa, trypanosomiasis of man and animals has curbed the realization of human ambitions and the mobilization of the continent’s vast resources.”   --Herbert S. Gasser [2]

 

The quotation from Herbert S. Gasser, a Nobel laureate and former director of the Rockefeller Institute for Medical Research, profoundly captures the impact of African trypanosomiasis as being a major barrier to economic and social development in many regions of the African continent.  African trypanosomiasis, commonly referred to as African sleeping sickness, is the result of a blood-borne protozoan infection in humans from one of two species—Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense. Tryaposoma belongs to the family Trypanosmatidae of the order Kinetoplastida.  Both of these parasites have similar pathogenic features, including the presentation of indistinguishable clinical manifestations in infected humans.  However, their epidemiological features differ greatly.  Throughout this website a distinction will be made when information applies to only one of the species.  All other information applies to both.  If you have questions or concerns, please feel free to contact the author, John Turnbull, at jht@stanford.edu.

 

HISTORY OF DISCOVERY

 

Although the symptoms of African sleeping sickness were documented by Atkins in 1742, the association of the clinical syndrome with its etiological agent, the trypanosome, was not documented until 1902 by Forde.[3]  In The Journal of Tropical Medicine, Forde chronicles his treatment of a 42 year-old European male colonialist who presented to his practice in the Gambia Colony in May 1901.  The patient complained of fever and malaise, leading Forde to make a preliminary diagnosis of malaria.  He initiated anti-malarial quinine treatment, but days later the patient’s conditioned had yet to improve.  Slides of the patient’s blood were prepared.  This examination ruled-out malaria due to a lack of malarial parasites found in the blood.  Only later, Dutton, a second physician from the Liverpool School of Tropical Medicine, made the identification of Trypanasoma brucei in the patient’s blood.[4]  Due to the probable location of the patient’s inoculation, this case can be attributed to the species T.b. gambiense.

 

The identification of T.b. rhodesiense as another species of trypanosome to cause African sleeping sickness was not documented until 1910.  Stephens and Fantham describe a strain of trypanosome observed in a blood smear of a patient who presented with symptoms of African trypanosomiasis.  The patient had no history of travel within a region known to be endemic with T.b. brucei, yet his blood smear clearly indicated a trypanosomal infection.  The novel morphology was believed to a be a new species of T. brucei.  Because the patient was believed to have been infected in Rhodesia (present day Zimbabwe), the new parasite was thus named—T.b. rhodesiense.[5]

 

Experiments published in 1912 by Kinghorn and Yorke proved that T.b. rhodesiense could be transmitted from human to animals by the tsetse fly.  They also concluded through their research that many game animals in East Africa, including waterbuck, hertebeest, impala, and warhog, served as reservoirs for T.b. rhodesiense in this region of the continent.[6]

 

 

Pathogenesis of T.b. gambiense & T.b. rhodesiense

 

MORPHOLOGY OF TRYPANOSOMES

 

A)                 B) 

 

 

The above slides are human blood smears of T. brucei stained with Giemsa stain (A) and a second one with differential interference contrast, as well, (B) to better visualize the flagellum.[7]  Only the Giemsa stain is required to locate trypanosomes and make a definitive diagnosis of African trypanosomiasis.  The two species of T. brucei are morphologically indistinguishable, but the differential diagnosis of the two infections can be made based on exposure history and serodiagnostic testing.  These slides highlight the characteristic organelles of the trypanosome, including the centrally located nucleus, the anterior kinetoplast—a second DNA-containing organelle, and the posterior flagellum that arises from a flagellar pocket to protect immunogenic sites.   The parasites range in size from 14 to 33 μm. 

 

LIFE CYCLE

 

1)     Infection of a human host occurs when a tsetse fly bites a human and transmits from its salivary glands the metacylic stage (the infective state) of the trypanosome.

2)     This metacylic stage quickly gives way to a blood-borne stage that begins a series of binary fission divisions at the site of inoculation.  This process leads to the formation of a primary chancre.

3)     The trypanosomes enter the bloodstream via the lymphatics and continue to multiply.  They also enter the CNS from here.

4)     A subsequent tsetse fly becomes infected by ingesting a blood meal that contains the trypanosomes from the infected host.

5)     In the gut of the fly, the trypanosomes transform into procyclic trypmastigotes that divide for 10 days.

6)     The organisms then migrate to the salivary glands and transform into epimastigotes, which later transform into metacyclic trypanosomes that can infect a new host.

 

VARIANT SURFACE GLYCOPROTEINS (VSGs)

 

T. brucei have a specialized mechanism to overcome the obstacles of the mammalian immune system.  Days after infection, host antibodies recognize surface glycoproteins that coat the protozoa—the antigenic determinants of the organism—and kill the organisms by labeling them destruction.  However a few protozoa escape destruction via a programmed system that changes their glycoprotein composition and thus enables them to evade immune recognition.  Again, days later the immune system recognizes this change and mounts an immune response against the new glycoprotein.  This cycle is repeated with a pattern of high parasite load followed by a period of low parasite load.  For this reason, patients exhibit an irregular pattern of high-grade fevers followed by an afebrile period throughout the course of a systemic infection.  For this reason, vaccine development has been thwarted.

 

CLINICAL PRESENTATION

 

Incubation Period: The first clinical manifestation of African trypanosomiasis occurs a few days after infection as a chancre at the site of tsetse fly inoculation.  This is due to the localized proliferation of the pathogens within the subcutaneous tissue.  Incubation period for T.b. rhodesiense may be two to three weeks, while the incubation period for the Gambian species may last several weeks to months.

 

A)         B)        C)

 

 

A teenage girl in Uganda with sleeping sickness exhibiting the characteristic chancre on her leg at the site of tsetse fly inoculation (A), and a woman in Uganda with a partially healed chancre just above her elbow (B).  Although (C) may look painful, chancres are generally painless with some associated tenderness.

 

Dissemination: With the conclusion of the incubation period, the organisms have already disseminated into the bloodstream, leading to the emergence of a characteristic intermittent fever pattern that correlates directly with high versus low levels of parasitemia.  The reason for the oscillating levels of parasite load is linked to the ability of the organisms to change their variable surface glycoproteins (VSGs) and evade the host’s immune system.  Lymphadenopathy, the swelling of lymph nodes, especially in the posterior cervical nodes (on the back of the neck) is characteristic sign of African sleeping sickness and is termed Winterbottom’s sign.

 

Invasion of the Central Nervous System:  Invasion of the central nervous system (CNS) occurs within several weeks in the Rhodesian species and months to even years in the Gambian species of trypanosomiasis.  Symptoms include headache, stiff neck, sleep disturbance, and depression, followed by progressive mental deterioration, focal seizures, tremors, and palsies.  This progresses to coma and the ultimate death of the patient often secondary to pneumonia or sepsis.  Without treatment, African trypanosomiasis is a universally fatal illness.

 

 

A)                           B)

 

A male patient in the finals stages of African sleeping sickness, ultimately ending with his death. (A)

(B) The neuropathology slide form a patient with encephalitis secondary to African trypanosomiasis.  The dots stained with purple indicate a highly dense population of lymphocytes, plasma cells and large macrophages within the blood vessel and diffusing into the surrounding tissue.  This would lead to an immune-mediated swelling of the central nervous system, ending with death.

 

 

 

Diagonsis

 

A history of travel within an endemic region and especially a memory of a bite from a tsetse fly are both key to a clinician’s ability to consider African sleeping sickness when encountering a patient outside an endemic region.  If exposure history has been documented, the definitive diagnosis of African trypanosomiasis is made by identifying the protozoa in the patient’s blood, cerebrospinal fluid, or aspirates of the lymph nodes.  Because this is primarily a tissue-dwelling organism examination of the bone marrow or lymph nodes may reduce the likelihood of a false negative compared to examination of the peripheral circulation.  To concentrate the trypanosomes in a sample, centrifugation is often advised.  An ELISA may also be used to identify antigens, as well as a new serodiagnostic tool termed the Card Agglutination Test for Trypanosomiasis (CATT).  Another test called card Indirect Agglutination Test (CIATT) tests for antigens rather than antibodies.  It has a high sensitivity and specificity and can distinguish between the two species of trypanosomes.  This latter test will allow for rapid and reliable data concerning the incidence of African trypanosomiasis—a key aspect of any prevention and control program.

 

A)                              B)

 

A doctor performing a spinal tap to examine the cerebrospinal fluid of a patient suspected to have an infection with African trypanosomiasis (A).  The Card Agglutination Test for Trypanosomiasis (CATT).  This inexpensive and rapid serodiagnostic test identifies those patients with antibodies against the organisms, indicating infection (B).

 

Treatment

 

Unless treated, African trypanosomiasis is a fatal illness.  The most effective treatment intervention for this disease must begin before the organism migrates into the CNS because the most effective drug does not cross the blood-brain barrier.  This drug, suramin, is administered intravenously and most often results in the full recovery of the patient.  Side effects include nausea, vomiting, pruritus (itching), uricaria (hives), hypesthesia (decreased sensitivity), photophobia (increased sensitivity to light), and peripheral neuropathy.  Most of these symptoms are not dangerous and disappear after a few days of treatment.  Pentamidine isethionate is an alternative therapeutic agent, but also has many side effects.

 

Melarsoprol is the drug of choice should the disease have progressed sufficiently to affect the central nervous system.  This drug is toxic and may lead to myocarditis, renal damage, peripheral neuropathy, encephalopathy, a Jarisch-Herxheimer reaction (an immune-mediated system reaction).  Approximately 5% of patients die from this treatment, while another 5% relapse.  Success rate may be increased by pretreatment with suramin.[8]  More recently, Difluormethylornithine (DFMO), known as eflornithine, has proven to more safely and efficaciously eliminate the protozoa from the blood stream and has thus been termed “the resurrection drug.”[9]

 

 

A)         B)        C)

 

 

(A)  Vials of melarsopral.  (B)  A 19 year-old girl dying from late-stage disease

(B)  and an adverse reaction to melarsopral.  (C)  A man receiving IV treatment with eflornithine.

 

 

 

Vector

 

                  

 

Two pictures of Glossina, the tsetse fly and vector of African trypanosomiasis[10]

 

The vector for both types of African trypanosomiasis is Glossina, often referred to as the tsetse fly (pictured above).  Biologists have identified 23 different species of Glossina, of which all but three will transmit the trypanosomal infection to mammals.  The flies generally measure 7 to 14 mm in length.  Currently, this species of flies are restricted to sub-Saharan Africa north of the Kalahari Dessert, which currently restricts the transmission of the disease to within this region.  However, with rapid and frequent intercontinental travel, the introduction of this species to naïve regions poses a threat. 

 

Tsetse flies are haematophagous—dependant on blood sucking to derive nutrients.  Different species of Glossina have different preferences for the source of their blood meal with some specifically preferring human blood and are therefore important vectors of the disease in human populations.  Both male and female flies feed on blood and are both vectors of the parasites.

 

 

Epidemiology

 

 

Geographic Distribution of African Trypanosomiasis by Country[11]

 

The distribution of African trypanosomiasis is completely linked to the range of its vector, the tsetse fly.  Due to the tsetse fly’s climatic restrictions the disease is restricted between the 14th latitude north and the 29th latitude south on the African continent.[12]  According to the World Health Organization, countries where the disease is currently epidemic include Angola, Democratic Republic of the Congo, Uganda & Sudan.  Countries with high levels endemicity of including Cameroon, Congo, Cote d’Ivoire, Central African Republic, Guinea, Mozambique, Tanzania, & Chad.  African sleeping sickness can also be found in low endemic levels in Benin, Burkina-Faso, Gabon, Ghana, Equatorial Guinea, Kenya, Mali, Nigeria, Togo, & Zambia.  Because of poor disease surveillance and reporting, epidemiological information in Burundi, Botswana, Ethiopia, Liberia, Namibia, Rwanda, Senegal, & Sierra-Leone is poorly understood.

 

The disease is a threat to more 60 million people throughout Africa.  However, currently only 3 to 4 million of these people are under surveillance, leading to the reporting of only 45,000 cases in 1999.  Epidemiologists estimate that between 300,00 and 500,000 cases actually occurred during that same time period.  Surveillance is not only essential to track disease trends to determine possible interventions, but also to identify infected individuals so that treatment may be initiated before the disease progresses to less treatable state.

 

There have been three major epidemics in Africa in the last century.  One between 1896 and 1906 in Uganda and the Congo Basin.  Another one in 1920 that incorporated several African countries, and finally one that started in 1970 and is still in progress across much of Africa.  Noted below is an epidemic curve from Uganda illustrating this most recent outbreak.

 

 

 

African trypanosomiasis cases in Uganda by year[13]

 

TRANSMISSION TRENDS BETWEEN SPECIES

 

The different species of human pathogenic trypanosomes have different epidemiological characteristics, but both depend on transmission by the tsetse fly.  T.b. gambiense is found only in West Africa and is transmitted solely from person-to-person via the tsetse fly vector.  The species of tsetse flies that transmit this strain are G. palpalis, which live near vegetation associated with drainage lines, rivers and other permanent bodies of water.  No reservoirs exist in this species of the disease.  On the other hand, T.b. rhodesiense, which is found in Eastern and Southern Africa, is transmitted by G. morsitans, G. pallidipes and G. swynnertoni.  It is primarily transmitted from person-to-animal and then back to person via the tsetse fly vector.  The infection of a human is probably the result of an ecological disturbance in the environment that forced an encounter between an infected fly and a human, rather than the natural animal host and reservoir cycle.  Reservoirs include domestic and wild ungulates, plus other game and wild-life found on the East African plain.  From an anthropocentric perspective, these animals act as an unlimited and uncontrollable reservoir for the trypanosomal infection.  Control measure are much more difficult to implement here because solely monitoring the human population is inadequate to prevent transmission.

 

A)             B)

 

Two examples of tsetse fly habitat from West Africa (A) and East Africa (B).

 

 

Conversely, if one were to identify and treat every case of African sleeping sickness in West African humans, theoretically transmission would fall below the level needed to sustain the pathogen.  However, the complete elimination of West African trypanosomiasis from the human population seems unlikely even in this idealized situation due to the extreme cost of such a program.  The decreased virulence of the Gambian trypanosome also helps the pathogen’s ability to successfully infect new human hosts.  Remember that someone with T.b. gambiense will progress to disease and death much more slowly than someone with the Rhodesian form.   This allows more opportunity for a tsetse fly to bite an infectious host to transmit the infection to another individual.  Essentially, in this humans asymptomatic humans act as a reservoir of future infection.

 

Impact of African Animal Trypanosomiasis

 

In addition to the parasite’s associated human morbidity and mortality, various species of trypanosomes, including T. duttonella vivax, T.d. congolense and T.b rhodesiense, infect other animals and produce a similar disease as seen in humans.  When found in cattle, this disease is called nagana.  African animal trypanosomiasis has had a profound impact on the ability for parts of Africa to sustain a highly productive livestock population on the African plains.  The Food and Agricultural Organization of the United Nations states, “Trypanosomiasis is probably the only disease which has profoundly affected the settlement and economic development of a major part of a continent.”  Of the approximately 7-10 million km2 of land that are infested by tsetse fly, only 20 million cattle are raised.  Under different circumstances, this land could support more than 140 million cattle and increase meat production by 1.5 million tons! [14]  

 

Clinical syndromes in animals are similar between the various species of pathogenic trypanosomes.  Infection can lead to death, extreme weight loss, reduced growth rate in young animals, and organ damage.  Fertility in males may also be decreased due to testicular damage.  The impact of this disease extends beyond the direct associated human morbidity and mortality, as it decreases economic viability and the nutritional potential of human populations.  Sadly, the decrease in nutrition and protein intake also decreases the overall human health in an endemic region.

 

 

Prevention and Control Strategies

 

Early detection and treatment of infected individuals is key to prevention and control especially in West Africa where no non-human reservoirs exist.  New diagnostic tools, including CATT and CIATT, should be used to actively survey a population for possible infection.  Once a pocket of infection has been identified, every effort must be made to find all cases and treat them accordingly.  The World Health Organization sponsors a program called The Programme for Surveillance and Control of African Trypanosomiasis.  Its strategies include coordinating one surveillance system for all endemic countries under and coordinating among various field agencies surveillance work.

 

Controversial measures to eradicate the vectors and reservoirs of infection have been undertaken by various NGOs and governments in Africa.  However, because the reservoirs serve an important role in the environment for both humans and the overall ecosystem these measures have been largely avoided.  Campaigns to limit human exposure to tsetse flies have been undertaken in the form of fly traps near human populations.  The poisoning and drainage of water sources in West Africa has also been undertaken, but this too has negative side effects that many say outweigh the benefit of such a program.

                    

 

Two tsetse fly traps to aid in the avoidance of fly-human contact

 

 

 

Useful Links

 

Centers for Disease Control Parasites Page

 

Ohio State Trypanosomiasis Page

 

World Health Organization's Disease Surveillance

 

World Health Organization Trypanosomiasis Info

 

Program Against African Trypanosomiasis (PAAT)

 

Also refer to footnotes.

 

 

A woman caring for her comatose husband who is dying of African trypanosomiasis, Uganda, 1990



[1] If not otherwise noted, all photos from http://www-nt.who.int/tropical_diseases/databases/imagelib.pl  (May 22, 2001)

[2] Gasser S.  The Bane of Tropical Africa.  Lancet.  1: 1091  1963. 

[3] Despommier DD, Gwadz RW, Hotez PJ  Parasitic Disease (3rd Edition) New York: Springer-Verlag, 1995.  196.

[4] Forde, R.M.  Some Clinical Notes on a European Patient whose Blood a Trypanosoma was Observed.  J of Trop Med  5:261-262, 1902.

[5] Stephens JWW, Fantham HB.  On the Peculiar Morphology of a Trypanosome from a Case of Sleeping Sickness and the Possibility of its being a New Species (T. rhodesiense).  Proc R Soc Lond  83:23-33, 1910.

[6] Kinghorn A, York W.  One the Transmission of Human Trypanosomes by Glossina morsitans, and on the Occurrence of Human Trypanosomes in Game.  Ann Trop Med Parasitol.  6:1-23, 1912.

[7] http://www.dpd.cdc.gov/dpdx/HTML/TrypanosomiasisAfrican.htm  (May 22, 2001)

[8] Desponmmier 201.

[9] http://www-nt.who.int/tropical_diseases/databases/imagelib.pl (May 22, 2001)

[10] http://www.biosci.ohio-state.edu/~parasite/trypanosoma.html (May 22, 2001)

[11] http://www.who.int/emc/diseases/tryp/trypanogeo.html  (May 22, 2001)

[12] Dumas M, Boa FY  Human African Trypanosomiasis.  Hand Book of Clinical Neurology: Microbial Disease Vol 8 (52), 339.

[13] http://www.who.int/emc-documents/surveillance/docs/whocdscsrisr2001.html/African_Trypanosomiasis/A_Trypanosomiasis.htm#Trends  (May 22, 2001)

[14] qtd. from Molyneux DH and Ashford RW.  The Biology of Trypanosoma and Leishmania, Parasites of Man and Domestic Animal.  New York: Taylor and Francis Inc, 1983.  p. 129.