INTRODUCTION:
Sleeping sickness or Human African Trypanosomiasis (HAT) is known to be a “neglected tropical disease”, caused by a protozoan parasite which belongs to the genus of Trypanosoma and transmitted by the bite of the blood sucking vector “tsetse fly” belonging to the genus Glossina. This parasite causes infection and is known to endanger many lives in sub-saharan Africa (Brun et al., 2010). This disease is more commonly caused by Trypanosoma brucei gambiense (T b gambiense) which is prominent in West Africa and less pathogenic form is T b rhodesiense observed in East Africa. It is a fatal disease leading to both morbidity and mortality if it’s left untreated or appropriate treatment is not provided. The disease caused by the T b rhodesiense usually lasts for a few weeks thus known to cause acute disease and T b gambiense leads to chronic disease known as “Gambian sleeping sickness” lasting upto 3 years. From the overall cases of HAT, 95-97% is caused by T b gambiense and 3-5% is with T b rhodesiense. The primary reservoir of T b gambiense are human beings and T b rhodesiense are animals like cattle’s (Pere et al., 2011).
In early stages of infection known as haemolytic phase of infection, the parasites invades the human host’s body system through the bite of the tsetse fly upon which the parasite spreads in the lymphatic system, circulatory system and systemic organs by multiplying in the body, In the later stage of infection i.e. encephalitic phase, the parasite is able to cross the blood brain barrier (BBB) attacking the central nervous system (CNS) contributing to multiple varieties of neurological symptoms (Kennedy and Peter, 2008). This fatal disease is targeted for the global elimination of the disease with new diagnostic methods, treatment with effective and safe medications and tools for controlling the vector (Brun et al., 2010).
The diagnostic methods that are able to discriminate between the early and the late stage is critical for analyzing and in relation with the effects of toxic drugs used for treating CNS related diseases. According to the WHO, the late stage of HAT is determined by the analyzing the Cerebrospinal fluid (CSF) which is screened by lumbar puncture (LP) and shows the presence of trypanosomes and indication of less number of WBC’s i.e. less than 5 WBC/mm3 (Kennedy and Peter, 2013). The drug therapy for treating early stage is proven to be effective and intravenous [IV] suramin provided for T b rhodesiense and intramuscular or IV pentamidine for T b gambiense which is mild toxic. But, the drugs currently used for treating the later stage of HAT are known to be very toxic. The effective first line drug caused by T b rhodesiense for CNS is Melarsoprol, painful to administer and induces post-treatment reactive encephalopathy (PTRE) in nearly about 10% of the cases where half are fatal. According to recent studies. Melarsoprol (arsenic containing agent) has indicated a fatality rate of 6% (Phillippe et al., 2017). The further article focuses on detailed studies of the HAT disease.
EPIDEMIOLOGY:
Based on the vector distribution, the occurrence of HAT is restricted. Its vector i.e. tsetse fly is observed particularly in Sub-Saharan Africa between 14N and 20S. The species and Subspecies of tsetse fly is divided into three groups having different abilities for the transmission in human population (Brun et al., 2010). On a worldwide scale, the extent of the cases seems to be negligible, but based on the characteristic features of the disease and focal distribution have extreme effects on socioeconomic status in the affected areas (Eric M et al.,2008). The transmission of the disease occurs as a result of the interaction between the human and the vector during the activities of hunting, fishing and farming. Various factors lead to the increased transmission rates such as war, poverty and population displacement (Eric M et al., 2008). The T b gambiense have resulted in chronic anthroponotic endemic disease in the regions of central and western Africa. T b gambiense is transmitted by tsetse flies of Glossina palpalis group and T b rhodesiense is transmitted via the Glossina morsitans group. In 2010, T b gambiense caused endemic in 24 countries of Central and Western Africa which included Uganda, Guinea, Angola, Central African Republic, Democratic Republic of the Congo, Chad whereas T b rhodesiense was reported to be endemic in 13 countries of Eastern and Southern Africa (Tanzania, Malawi, Central Uganda). The sleeping sickness epidemic devastated Africa with 300 000–500 000 deaths between 1896 and 1906 that affected Uganda and Kenya. A second major outbreak occurred between 1920 and the late 1940s, which led to development of control strategies (Barrett and Michael, 2006). According to reports in 2004, 50 000–70 000 new cases was observed.
TRYPANOSOMA:
Trypanosomes belong to the Trypanosomatidae family and the genus Trypanosoma. These are unicellular organisms that cause HAT in humans. In the initial stage, they circulate in the blood and lymphatic system and at later stages they are able to cross the Blood brain barrier so are observed in CNS and brain parenchyma. This parasite evades the human immune system and modifies due to which protection from the immune system is not provided leading to immunopathology disorders. A surface coat is present around the Trypanosomes which is composed of glycoproteins protecting them from the lytic factors in human plasma, thus assisting in escaping the immune reactions. When the infection begins, the immune system of the host recognizes the glycoproteins which triggers the production of IgG and IgM antibodies. As a result, IgM level increases in the body with trypanosome-specific antibodies and non-specific immunoglobulin produced by the induction of the activation of B cells by cytokines. This sudden rise in IgM is an important feature of HAT. The parasitemia is decreased by these specific antibodies that are produced by neutralization of trypanosomes, but some of them are able to escape this neutralization by antibodies. Some subset of the trypanosomes have the ability to change their surface coat with new variant glycoproteins, thus are not affected by the antibodies circulating in the body. This leads to proliferation of the parasite until new antibodies are generated against those new variant trypanosomes with new glycoproteins.
This is repeated every time with newly formed variants of trypanosomes, so the immune system of the host fails to attack the trypanosomes leading to increased infection (Philippe and Bernard, 2006). The change of the surface glycoproteins is known as antigenic variability and as trypanosomes have high degree of antigenic variability, the development of the vaccine is difficult to achieve. Some antibodies are produced against the auto-antigens which leads to non-specific polyclonal activation of B cells producing natural auto-antibodies and antigen driven antibodies are also induced by molecular mimicry (Sambella et al., 2004). The variant glycoproteins are also capable of dysfunctioning the cytokine network and because of all the contributory effects there is an immunosuppression with collateral tissue damage. For parasite growth essential growth factors are required such as L-ornithine produced by the induction of the host arginase. It also leads to depletion of the L-arginine which is a substrate for nitric oxide (NO) synthase, thus inhibiting NO generation (Philippe et al, 2003).
CLINICAL FEATURES:
As there are two successive stages of the infection i.e. early stage known as hemolymphatic stage and the late stage known as meningo-encephalitic stage, the parasite invades the CNS causing sleeping sickness and if left untreated it is fatal i.e. leading to death or coma. A chancre is observed after the tsetse bite in 20% of the patients infected with T b rhodesiense which is indication of initial lesion at the site of bite. This causes local erythema, heat, oedema and tenderness. The first stage of T b gambiense infection is chronic causing headache, skin lesions, intermittent fever, oedema of the face and extremities, rubbery lymphadenopathies, severe pruritus with scratching and splenomegaly or hepatomegaly. Skin eruptions are occasionally observed. The early occurrence of myocarditis is considered to be a prognostic event (Johannes et al., 2007). Deep hyperaesthesia is observed known as Kerandel’s sign. The endocrinal disorder and neuro-psychiatric disorder is the clinical sign of the second stage of HAT. The dysregulation of the circadian rhythm of the sleep–wake cycle leads to sleep disorders and a fragmented sleeping pattern is observed (Kennedy and peter, 2006).
The neurological symptoms associated with the] is disease are tremor, akinesia or dyskinesia, fasciculations, speech disorders, diffuse hyperpathia, general motor weakness, confusion and abnormal movements. The first manifestation of the disease is by the dominance of Psychiatric symptoms (A L et al., 2000). The complications in thyroid and adrenocortical function indicates endocrine disorders that may be in the form of hyperfunction or hypofunction. The individuals infected with T b gambiense show a great genetic diversity of groups of trypanosomes (V et al., 2002). The disturbances in the consciousness with progressive dementia is associated with central nervous system demyelination and atrophy which is a feature of the last stage of the disease. This results in the death of patients from opportunistic infections.
DIAGNOSIS:
- Diagnosis of T b gambiense HAT:
Diagnosis of T b gambiense HAT is based on three steps i.e. screening, parasitological confirmation and staging (Francois et al., 2005). A rapid serological screening test for HAT control programmes is Card Agglutination Test for trypanosomiasis (CATT) (E et al., 1978). CATT shows high sensitivity for undiluted blood i.e. (87-98%) and results in negative test results. Thus even if CATT specificity is 95%, it requires parasitological confirmation. In non-endemic countries serological tests such as ELISA and immunofluorescence are used. The parasitological test is done by the microscopic examination of the smear of inoculated chancre, cervical lymph node fluid obtained by puncture or blood. Blood concentration techniques are used as there may be less number of parasites. The widely used technique for this purpose is capillary tube centrifugation technique and microhaematocrit centrifugation technique (Woo and P T, 1970). Six to eight capillaries tubes for examination should be used for microhematocrit technique. This technique may become difficult because of the presence of microfilaria. The most sensitive technique for detection of trypanosome is the miniature-anion exchange centrifugation used for separating the trypanosomes from venous blood and later concentrating them in a collecting tube by centrifugation (P et al., 2006). For detecting the trypanosomes nucleic acids, PCR technique can be used which is more sensitive but needs standardization and diagnostic validation. Staging depends on the CSF examination after lumbar puncture as treatment is based on the infection stage. The high IgM levels in the CSF indicate a reliable marker in neurological involvement (Lejon and Büscher, 2005).
- Diagnosis of T b rhodesiense HAT:
For the diagnosis of T b rhodesiense HAT same stages are followed as of T b gambiense HAT i.e. screening, diagnostic confirmation and staging. The difference in the diagnostic testing between the both are as follows: i) the screening test is based on identifying the non-clinical features such as fever and history of exposure. ii) The parasitological confirmation becomes easier as the density of circulating trypanosomes in the blood are high, thus easy detection iii) test such as coagulation test, the platelet and haemoglobin count indicates the frequent alteration of biological indices.
TREATMENT:
Treatment of T b gambiense HAT:
For several decades, the first stage of HAT by T b gambiense has been treated by using Pentamidine. It is administered intravenously by slow infusion for 7 days or intramuscularly. Hypoglycemia, hypotension, aseptic or septic abscess are some of the adverse effects at the site of injection. The patients are provided with sweet foods and drinks before the injection and instructed to lie down for 1 hr after injection. At the second stage of T b gambiense HAT, an arsenic-based derivative i.e. Melarsoprol is injected. This drug has many adverse effects such as peripheral neuropathy,skin rash, encephalopathic syndrome, hepatic toxicity, vein sclerosis and acute phlebitis, thus have been reported for more failure rates.Another drug eflornithine (a-difluoromethylornithine or DFMO)which is recognized as more safer than melarsoprol after years of studies, it was implemented for administration after 2000 (Manica et al., 2009). Thus Melarsoprol is eventually replaced by eflornithine for first line treatment.
Treatment of T b rhodesiense HAT:
A complex dose plan lasting upto 30 days with Suramin is administered for the first stage of T b rhodesiense. The adverse effects caused by this drug is peripheral neuropathy, bone marrow toxicity and nephrotoxicity that are reversible and mild. For the second stage, the treatment is dependent only on Melarsoprol because T b rhodesiense is innately resistant to eflornithine.
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