African trypanosomiasis
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African trypanosomiasis
Classification and external
resources
Trypanosoma forms in a blood
smear.
ICD-10 B56.
ICD-9 086.5
DiseasesDB 29277 13400
MedlinePlus 001362
eMedicine med/2140
MeSH D014353
Human African trypanosomiasis or Sleeping sickness is a parasitic disease of people and
animals, caused by protozoa of the species Trypanosoma brucei and transmitted by the tsetse
fly.[1] The disease is endemic in some regions of Sub-Saharan Africa, covering about 36 countries
and 60 million people. It is estimated that 50,000 to 70,000 people are currently infected, the
number having declined somewhat in recent years.[2] Three major epidemics have occurred in
recent history, one lasting from 1896–1906 and the other two in 1920 and 1970. In 2008 there
was an epidemic in Uganda.[3]
Contents
[hide]
• 1 Symptoms and clinical features
• 2 History
• 3 Geographic distribution and epidemiology
• 4 Life cycle
• 5 Laboratory diagnosis
• 6 Treatment
○ 6.1 First line, first stage
○ 6.2 First line, second stage
○ 6.3 Resistant disease
○ 6.4 Outdated protocols
○ 6.5 History and research
• 7 Drug targets and drug discovery
• 8 Prevention and control
• 9 See also
• 10 References
• 11 External links
[edit] Symptoms and clinical features
Winterbottom's sign - Swollen lymph nodes along back of neck in child with early
trypanosomiasis
Symptoms begin with fever, headaches, and joint pains. As the parasites enter through both the
blood and lymph systems, lymph nodes often swell up to tremendous sizes. Winterbottom's sign,
the tell-tale swollen lymph nodes along the back of the neck, may appear. If untreated, the
disease slowly overcomes the defenses of the infected person, and symptoms spread to include
anemia, endocrine, cardiac, and kidney diseases and disorders. The disease then enters a
neurological phase when the parasite passes through the blood-brain barrier. The symptoms of
the second phase give the disease its name; besides confusion and reduced coordination, the
sleep cycle is disturbed with bouts of fatigue punctuated with manic periods progressing to
daytime slumber and night-time insomnia. Without treatment, the disease is invariably fatal, with
progressive mental deterioration leading to coma and death. Damage caused in the neurological
phase can be irreversible.[4]
In addition to the bite of the tsetse fly, the disease is contractible in the following ways:
• Mother to child infection: the trypanosome can cross the placenta and infect the fetus,
causing prenatal death.
• Laboratories: accidental infections, for example, through the handling of blood of an
infected person and organ transplantation, although this is uncommon.
• Blood transfusion
[edit] History
The condition has been present in Africa since at least the 14th century, and probably for
thousands of years before that. The causative agent and vector were not identified until 1902–
1903 by Sir David Bruce, and the differentiation between the subspecies of the protozoa was not
made until 1910. The first effective treatment, Atoxyl, an arsenic-based drug developed by Paul
Ehrlich and Kiyoshi Shiga, was introduced in 1910 but blindness was a serious side effect.
Numerous drugs designed to treat the disease have been introduced since then.
There have been three severe epidemics in Africa in recent history: one between 1896 and 1906,
mostly in Uganda and the Congo Basin, one in 1920 in several African countries, and one that
began in 1970 and is still in progress. The 1920 epidemic was arrested due to mobile teams
systematically screening millions of people at risk. The disease had practically disappeared
between 1960 and 1965. After that success, screening and effective surveillance were relaxed
and the disease has returned in endemic form in several places during the last thirty years. [5]
[edit] Geographic distribution and epidemiology
Deaths per 100,000 population due to African trypanosomiasis by country in 2002 [6].
The disease is found in two forms, depending on the parasite, either Trypanosoma brucei
gambiense or Trypanosoma brucei rhodesiense. T. b. gambiense is found in central and western
Africa; it causes a chronic condition that can extend in a passive phase for months or years
before symptoms emerge. T. b. rhodesiense, is the acute form of the disease but has a much more
limited range. It is found in southern and eastern Africa; its infection emerges in a few weeks and
is more virulent and faster developing. According to recent estimates, the disability adjusted life
years (9 to 10 years) (DALYs) lost due to sleeping sickness are 2.0 million.[7] Recent estimates
indicate that over 60 million people living in some 250 locations are at risk of contracting the
disease, and there are about 300,000 new cases each year.[8] The disease has been recorded as
occurring in 36 countries, all in sub-Saharan Africa. It is endemic in southeast Uganda and
western Kenya and kills more than 40,000 Africans a year.[9]
Humans are the main reservoir for Trypanosoma brucei gambiense, but this species can also be
found in pigs and other animals. Wild game animals and cattle are the main reservoir of T. b.
rhodesiense.
Horse-flies (Tabanidae) and stable flies (Muscidae) possibly play a role in transmission of
Nagana (the animal form of sleeping sickness) and the human disease form.[10]
[edit] Life cycle
Life cycle of the Trypanosoma brucei parasites. Source: CDC
The tsetse fly is large, brown and stealthy. While taking blood from a mammalian host, an
infected tsetse fly (genus Glossina) injects metacyclic trypomastigotes into skin tissue. The
parasites enter the lymphatic system and pass into the bloodstream
1. Inside the host, they transform into bloodstream trypomastigotes
2. are carried to other sites throughout the body, reach other blood fluids (e.g., lymph, spinal
fluid), and continue the replication by binary fission
3. The entire life cycle of African Trypanosomes is represented by extracellular stages. A
tsetse fly becomes infected with bloodstream trypomastigotes when taking a blood meal
on an infected mammalian host
4. In the fly's midgut, the parasites transform into procyclic trypomastigotes,
5. multiply by binary fission,
6. leave the midgut, and
7. transform into epimastigotes
8. The epimastigotes reach the fly's salivary glands and continue multiplication by binary
fission.
The cycle in the fly takes approximately 3 weeks to progress.
[edit] Laboratory diagnosis
Two areas from a blood smear from a patient with African trypanosomiasis. Thin blood smear
stained with Giemsa. Typical trypomastigote stages (the only stages found in patients), with a
posterior kinetoplast, a centrally located nucleus, an undulating membrane, and an anterior
flagellum. The two Trypanosoma brucei species that cause human trypanosomiasis, T. b.
gambiense and T. b. rhodesiense, are indistinguishable morphologically. The trypanosomes
length range is 14 to 33 µm, Source: CDC
The diagnosis rests upon demonstrating trypanosomes by microscopic examination of chancre
fluid, lymph node aspirates, blood, bone marrow, or, in the late stages of infection, cerebrospinal
fluid. A wet preparation should be examined for the motile trypanosomes, and in addition a
smear should be fixed, stained with Giemsa (or Field), and examined. Concentration techniques
can be used prior to microscopic examination. For blood samples, these include centrifugation
followed by examination of the buffy coat; mini anion-exchange/centrifugation; and the
Quantitative Buffy Coat (QBC) technique. For other samples such as spinal fluid, concentration
techniques include centrifugation followed by examination of the sediment. Isolation of the
parasite by inoculation of rats or mice is a sensitive method, but its use is limited to T. b.
rhodesiense. Antibody detection has sensitivity and specificity that are too variable for clinical
decisions. In addition, in infections with T. b. rhodesiense, seroconversion occurs after the onset
of clinical symptoms and thus is of limited use.
Three similar serological tests are available for detection of the parasite; the micro-CATT, wb-
CATT, and wb-LATEX. The first uses dried blood while the other two use whole blood samples.
A 2002 study found the wb-CATT to be the most efficient for diagnosis, while the wb-LATEX is
a better exam for situations where greater sensitivity is required.[11]
[edit] Treatment
[edit] First line, first stage
The current standard treatment for first stage disease is:
• Intravenous pentamidine (for T.b. gambiense); or
• Intravenous suramin (for T.b. rhodesiense)
The drug Eflornithine — previously used only as an alternative treatment for sleeping sickness
due to its labour-intensive administration — was found to be safe and effective as a first-line
treatment for the disease in 2008, according to the Science and Development Network's Sub-
Saharan Africa news updates. [1]. Researchers tracked over 1,000 adults and children at a centre
in Ibba, Southern Sudan—the first use of eflornithine on a large scale— and it was highly
effective in treating the issue.
According to a treatment study of Trypanosoma gambiense caused human African
trypanosomiasis, use of eflornithine (DMFO) resulted in fewer adverse events than treatment
with melarsoprol. [12]
All patients should be followed up for two years with lumbar punctures every six months to look
for relapse.
[edit] First line, second stage
The current standard treatment for second stage (later stage) disease is:
• Intravenous melarsoprol 2.2 mg/kg daily for 10 consecutive days.[13]
Alternative first line therapies include:
• Intravenous melarsoprol 0.6 mg/kg on day 1, 1.2 mg/kg iv melarsoprol on day 2, and 1.2
mg/kg/day iv melarsoprol combined with oral 7.5 mg/kg nifurtimox twice a day on days
3 to 10;[14] or
• Intravenous eflornithine 50 mg/kg every six hours for 14 days.[15]
[edit] Resistant disease
In areas with melarsoprol resistance or in patients who have relapsed after melarsoprol
monotherapy, the treatment should be:
• melarsoprol and nifurtimox, or
• eflornithine
[edit] Outdated protocols
The following traditional regimens should no longer be used:
• (old "standard" 26-day melarsoprol therapy) Intravenous melarsoprol therapy (3 series of
3.6 mg/kg/day intravenously for 3 days, with 7-day breaks between the series) (this
regimen is less convenient and patients are less likely to complete therapy);[16]
• (incremental melarsoprol therapy) 10-day incremental-dose melarsoprol therapy (0.6
mg/kg iv on day 1, 1.2 mg/kg iv on day 2, and 1.8 mg/kg iv on days 3–10) (previously
thought to reduce the risk of treatment-induced encephalopathy, but now known to be
associated with an increased risk of relapse and a higher incidence of
encephalopathy)[14][16];
[edit] History and research
Suramin was introduced in 1920 to treat the first stage of the disease. By 1922, Suramin was
generally combined with Tryparsamide (another pentavalent organo-arsenic drug) in the
treatment of the second stage of the gambiense form. It was used during the grand epidemic in
West and Central Africa in millions of people and was the mainstay of therapy until 1969.
Pentamidine, a highly effective drug for the first stage of the disease, has been used since 1939.
During the fifties, it was widely used as a prophylactic agent in Western Africa, leading to a
sharp decline in infection rates. At the time, it was thought that eradication of the disease was at
hand.
The organo-arsenical melarsoprol (Arsobal) was developed in the 1940s, and is effective for
patients with second stage sleeping sickness. However, 3 - 10% of those injected have reactive
encephalopathy (convulsions, progressive coma, or psychotic reactions), and 10 - 70% of such
cases result in death; it can cause brain damage in those who survive the encephalopathy.
However, due to its effectiveness, melarsoprol is still used today. Resistance to melarsoprol is
increasing, and combination therapy with nifurtimox is currently under research.
Eflornithine (difluoromethylornithine or DFMO), the most modern treatment, was developed in
the 1970s by Albert Sjoerdsmanot and underwent clinical trials in the 1980s. The drug was
approved by the United States Food and Drug Administration in 1990, but Aventis, the company
responsible for its manufacture, halted production in 1999. In 2001, however, Aventis, in
association with Médecins Sans Frontières and the World Health Organization, signed a long-
term agreement to manufacture and donate the drug.
An international research team working in the Democratic Republic of the Congo, New Sudan
and Angola involving Immtech International and University of North Carolina at Chapel Hill
have completed a Phase IIb clinical trial and commenced a Phase III trial in 2005 testing the
efficacy of the first oral treatment for Sleeping Sickness, known at this point as "DB289". [17] [18]
Trypanosomiasis vaccines are undergoing research.
[edit] Drug targets and drug discovery
The genome of the parasite has been decoded and several proteins have been identified as
potential targets for drug treatment. The decoded DNA also revealed the reason why generating a
vaccine for this disease has been so difficult. T. brucei has over 800 genes that manufacture
proteins that the disease mixes and matches to evade immune system detection.[19]
Recent findings indicate that the parasite is unable to survive in the bloodstream without its
flagellum. This insight gives researchers a new angle with which to attack the parasite.[20]
A new treatment based on a truncated version of the apolipoprotein L-1 of high density
lipoprotein and a nanobody has recently been found to work in mice, but has not been tested in
humans.[21]
The cover story of the August 25, 2006 issue of Cell journal describes an advance; Dr. Lee Soo
Hee and colleagues, working at Johns Hopkins, have investigated the pathway by which the
organism makes myristate, a 14-carbon length fatty acid. Myristate is a component of the variant
surface glycoprotein (VSG), the molecule that makes up the trypanosome's outer layer. This
outer surface coat of VSG is vital to the trypanosome's avoidance of immunological capture. Dr.
Lee and colleagues discovered trypanosomes use a novel fatty acid synthesis pathway involving
fatty acid elongases to make myristate and other fatty acids.
[edit] Prevention and control
For in depth information on prevention of the disease via tsetse fly control see Tsetse fly control.
Prevention and control focus on, where it is possible, the eradication of the parasitic host, the
tsetse fly. Two alternative strategies have been used in the attempts to reduce the African
trypanosomiases. One tactic is primarily medical or veterinary and targets the disease directly
using monitoring, prophylaxis, treatment, and surveillance to reduce the number of organisms
which carry the disease. The second strategy is generally entomological and intends to disrupt
the cycle of transmission by reducing the number of flies. Instances of sleeping sickness are
being reduced by the use of the sterile insect technique.
Regular active surveillance, involving case detection and treatment, in addition to tsetse fly
control, is the backbone of the strategy for control of sleeping sickness. Systematic screening of
communities in identified foci is the best approach as case-by-case screening is not practically
possible in highly endemic regions. Systematic screening may be in the form of mobile clinics or
fixed screening centres where teams travel daily to the foci. The nature of gambiense disease is
such that patients do not seek treatment early enough because the symptoms at that stage are not
evident or serious enough to warrant seeking medical attention, considering the remoteness of
some affected areas. Also, diagnosis of the disease is difficult and most health workers may not
be able to detect it. Systematic screening allows early-stage disease to be detected and treated
before the disease progresses, and removes the potential human reservoir.[22] There is a single
case report of sexual transmission of West African sleeping sickness,[23] but this is not believed to
be an important route of transmission
