Trypanosomiasis – Update on Laboratory Diagnosis and Treatment

Abstract

Trypanosomes are hemoflagellates that reside in peripheral blood and tissues of the host caused by infection with protozoan parasites belonging to the genus Trypanosoma. Types: Human African Trypanosomiasis – HAT (sleeping sickness) &American Trypanosomiasis (Chagas’ disease). Metacyclic trypomastigotes is the infective form. C/F includes Fever, headaches, irritability, extreme fatigue, swollen lymph nodes, aching muscles and joints. Chronic Chagas’: cardiomyopathy with congestive heart failure. Diagnosis: examination of blood smears during the acute disease usually shows trypomastigotes. Serologic testing is used for screening purposes only. PCR of kDNA may also be used. Isothermal amplification technology (i.e., RPA or LAMP), possibly enhanced by combining it with a highly specific CRISPR-Cas step, will fulfil all the requirements of a modern target product profile for HAT diagnosis. Drugs used are Pentamidine, Suramin (first stage) & Melarsoprol, Eflornithine, Nifurtimox (second stage). Fexinidazole is used in both stages. Newer drugs include Pafuramidine & Acoziborole

1. Introduction

Trypanosomes are unicellular protozoa that have been linked to human disease for more than 300 million years. They are common parasites of animals, including mammals, birds, fish, amphibians, plants, and insects. All around the planet, these trypanosomes are prevalent. But fortunately, there aren’t many harmful species [1]. There are more than 20 species in the genus Trypanosoma, but only a small number of them, including Trypanosoma cruzi (American Trypanosome), and the two African trypanosome subspecies, Trypanosoma brucei gambiense and T. b. rhodesiense, may infect people. Hemoflagellates called trypanosomes live in the host’s tissues and peripheral blood. Trypanosomiasis is the name for the infection caused by the protozoan parasites of the genus Trypanosoma [2].

African Trypanosomiasis infection in humans is widely known as sleeping sickness or as Human African Trypanosomiasis (HAT), and trypanosomiasis infection in cattle is known as Nagana (meaning ‘loss of spirit’ in the Zulu language). The protozoan parasite is transmitted by tsetse flies, which are found mainly in sub-Saharan Africa. The disease is of two types: West African trypanosomiasis and East African trypanosomiasis. The West African type is chronic, whereas the East African type has an acute presentation [1].

American Trypanosomiasis, commonly known as Chagas’ Disease, is caused by Trypanosoma cruzi, a chronic human infection that is geographically prevalent throughout Latin America, extending within the southern borders of the USA [1, 3].

Humans are naturally resistant to the majority of Trypanosoma species. However, infrequently, some uncommon species infect humans. 19 cases of atypical human trypanosomoses (a-HT), which were all thought to be non-infectious to humans, have been linked to the trypanosomes T. b. brucei, T. vivax, T. congolense, T. evansi, and T. lewisi. T. evansi and T. lewisi have surfaced as possible human pathogens recently [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19].

2. Taxonomy

Domain: Eukaryota

Kingdom: Protista

Phylum: Protozoa

Subphylum: Sarcomastigophora

Order: Kinetoplastida

Suborder: Trypanosomatina

Family: Trypanosomatidae

Genus: Trypanosoma

Selected species: [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23]

• T. brucei, causes sleeping sickness in humans and nagana in cattle

• T. cruzi, causes Chagas disease in humans

• T. congolense, causes nagana in ruminant livestock, horses and a wide range of wildlife

• T. equiperdum, in South American horses, transmitted via Tabanidae,

• T. evansi, causes one form of the disease surra in certain animals including camel

• T. rangeli, believed to be nonpathogenic to humans

• T. simiae, causes nagana in pigs. Its main reservoirs are warthogs and bush pigs

• T. suis, causes a different form of surra. Very rarely isolated

• T. vivax, causes the disease nagana, mainly in West Africa, although it has spread to South America

3. Epidemiology

3.1 African trypanosomiasis

T. b. rhodesiense is only found in eastern and southern Africa, whereas T. b. gambiense is endemic in western and central Africa. 24 nations in west and central Africa are home to T. b. gambiense, known as West African sleeping sickness. Currently, 97% of sleeping sickness cases that are documented are due to the chronic illness caused by West African sleeping sickness. Focused areas of eastern and south-eastern Africa are where T. b. rhodesiense, also known as the East African sleeping disease, is found. It causes an acute infection. Except in Uganda, where both subspecies are co-endemic (T. b. gambiense is primarily found in the centre of the country, near the borders with South Sudan and the Democratic Republic of the Congo), the ranges of the two species do not overlap [24].

T. brucei historically caused epidemics in the late 1800s and early 1900s that resulted in the deaths of approximately a million people. Early vector control and disease surveillance implemented by colonial nations helped the disease get close to elimination in 1960. The surveillance activities, however, were stopped after independence, which caused a return with a high incidence in the late 1990s [24].

Decline in reported cases: The number of trypanosomiasis cases that have been documented has decreased in sub-Saharan Africa. In contrast to the 1,000 instances recorded in 2020, nearly 30,000 new cases were reported in the year 2000. This decrease in incidence is attributable to ongoing efforts to control the tsetse fly vector as well as early detection and fast disease treatment [25].

3.2 American trypanosomiasis

Initially, American trypanosomiasis, often known as Chagas disease (CD), was only found in the Americas. The epidemiology pattern of CD has transformed from a primarily rural to an urban disease over the last few decades. Population movement, urbanisation, and emigration were the main causes of this. All of these reasons have led to an upsurge in instances being found in Canada and the United States of America. Numerous European, some African, Eastern Mediterranean, and Western Pacific nations have also reported cases. The WHO has estimated that 75 million individuals are at risk of infection due to the high number of cases that go undetected or untreated, as well as the locations where transmission is still prevalent [26, 27].

T. cruzi infection affects 6–7 million people worldwide. Chagas disease is mostly found in 21 nations in continental Latin America, where it is endemic, and it is primarily spread to people through contact with the faeces and/or urine of infected triatomine bugs (vector-borne transmission) [26, 27].

Decline in reported cases: The prevalence of Chagas disease has declined in several endemic nations, primarily Brazil and Argentina. This is linked to enhanced management strategies that target lowering insect vector numbers as well as blood supply screening. 6.4 million cases of CD were reported globally in 2019, which is less than the 7.2 million cases that were recorded in 1990. This indicates a drop in the prevalence of 11.3% during the previous three decades [28].

3.3 Atypical human trypanosomoses (a-HT): Asian epidemiology

3.3.1 Trypanosoma evansi

1. In 2005, T. evansi was discovered in a 45-year-old cattle farmer from Nagpur (Maharasthra State), India, who had never travelled outside of the district. Suramin, a medication used to treat early-stage T. b. rhodesiense HAT and known to be effective against T. evansi, was administered to the patient. Because no parasites could be found in the blood after therapy and the patient’s overall health improved, the treatment was successful. This was the first report of a T. evansi infection in humans.

2. A 38-year-old Vietnamese woman was identified as having a T. evansi infection in 2015. She had previously visited a rural province in the Central Highlands of Vietnam. She has no immunological risk factors for Trypanosoma infection that have been previously identified. The patient’s 2–3-month postpartum status at the time of exposure was the sole known risk factor, which is also a risk factor for numerous infectious illnesses. Since Suramin was not yet accessible in Vietnam, she was treated with amphotericin B. According to data from a mouse T. cruzi model, amphotericin B may have trypanostatic effects but weak trypanocidal effects. The effectiveness of amphotericin B for T. evansi therapy is still unclear because the patient relapsed 6 weeks after starting treatment. But suramin therapy produced a quick and lasting recovery. Additionally, two mutations in codons 142 and 266 of the gene producing apolipoprotein L1 (APOL1) have been linked to T. evansi susceptibility in an Indian patient in the past [11], despite the fact that this patient lacked the genetic alterations linked to APOL1 deficiency. This is the first instance of T. evansi infection in an Asian patient who was previously healthy and did not have APOL1 deficiency, according to the paper. Following field studies revealed a significant incidence of bovids in the patient’s immediate surroundings, along with clinical and molecular proof of T. evansi infection. Therefore, it is likely that the illness was acquired through direct wound inoculation from infected cattle flesh [29].

4. Transmission and life cycle

4.1 African trypanosomes

4.1.1 The infective form is the metacyclic trypomastigote

See (Figure 1).

Figure 1.

The life cycle of T. brucei [30].

The cycle in the fly takes approximately 3 weeks. When the tsetse fly bites another host, it injects the metacyclic trypomastigotes in its saliva, transmitting the disease to the new host [31].

Rarely, T. b. gambiense may be acquired congenitally if the mother is infected during pregnancy.

4.2 American trypanosomes

4.2.1 The infective form is the metacyclic trypomastigote

An infected triatomine insect vector (or “kissing bug”) belonging to the genera Triatoma, Rhodnius, or Panstrongylus feeds on blood and excretes trypomastigotes near the bite incision. Through a lesion or intact mucosal membranes, trypomastigotes enter the host. Inside the host, trypomastigotes invade cells close to the inoculation site, where they undergo differentiation into intracellular amastigotes.

These amastigotes multiply through binary fission, differentiate into trypomastigotes, and then enter the bloodstream as trypomastigotes. Trypomastigotes infect cells from diverse tissues and subsequently transform into intracellular amastigotes at new infection locations.

Clinical manifestations can result from this infective cycle. Trypomastigotes in the circulation do not replicate (unlike African trypanosomes). Only when the parasites penetrate another cell or are ingested by another vector does replication resume. The “kissing bug” becomes infected by feeding on human or animal blood containing parasites that are in circulation. In the midgut of the vector, the ingested trypomastigotes transform into epimastigotes [32].

In the midgut, the parasites proliferate and differentiate; in the hindgut, they transform into infective metacyclic trypomastigotes. Trypanosoma cruzi can also be transmitted via blood transfusions, organ transplants, transplacentally (from mother to unborn child), and laboratory accidents.

5. Clinical manifestations

5.1 African trypanosomiasis

Trypanosoma brucei gambiense, which causes West African trypanosomiasis, and Trypanosoma brucei rhodesiense, which causes East African trypanosomiasis, are the two main types of the disease in Africa. While the clinical characteristics of the two types differ in several ways, they also have many things in common, such as:

1. Early Stage Symptoms: Non-specific early stage symptoms, which might include fever, headaches, joint pain, muscular weakness, weariness, itching, and swollen lymph nodes, usually start at the beginning of the disease [33, 34].

2. Late Stage Symptoms: As the illness worsens, neurological symptoms such as confusion, altered behaviour, disturbed sleep, tremors, seizures, trouble walking, and poor coordination may appear. Abdominal pain, diarrhoea, vomiting, and severe weight loss are some of the signs of late-stage East African trypanosomiasis, which advances faster than the West African variety [33, 34].

3. Cardiac symptoms: The trypanosome parasite can enter the heart and cause heart failure and cardiac arrhythmias, which can result in rapid death [33, 34].

4. Cutaneous symptoms: Skin changes, rashes, and itching are all possible manifestations of West African trypanosomiasis [33, 34].

5. Encephalitis: Once an infection has spread to the central nervous system, it can cause progressive disorientation, personality changes, and other neurologic issues. Rarely, acute encephalitis, with fever, coma, and seizures, can manifest as a severe form of the illness. If the infection is not treated, it gets worse and eventually leads to death within months [34, 35].

Immunosuppression: Trypanosomiasis can cause immunological suppression, which raises the risk of contracting other opportunistic illnesses [34, 35].

5.2 American trypanosomiasis

This disease can have acute and chronic phases, each with a range of clinical features:

The majority of Chagas disease patients only experience mild, flu-like symptoms during the acute phase, which can extend for many weeks. These signs and symptoms include a fever, exhaustion, headache, body aches, and swelling at the bite site or the eye (if that was the parasite’s point of entry) [36].

• During the acute phase, a small percentage of infected people may experience severe symptoms such as myocarditis (inflammation of the heart muscle), pericarditis (inflammation of the heart’s protective membrane), meningoencephalitis (inflammation of the brain and surrounding tissue), and hepatosplenomegaly (enlargement of the liver and spleen) [36, 37].

• About 30% of those who contract Trypanosoma cruzi go on to develop chronic Chagas disease. The majority of those who have chronic Chagas’ disease don’t exhibit any symptoms; however, some may experience severe illness decades after infection [36, 37]. The heart, gastrointestinal tract, and brain system are just a few of the various organs that chronic Chagas’ illness can impact.

• The most serious and frequent complication of persistent Chagas’ illness is cardiac involvement. Arrhythmias, chest pain, palpitations, shortness of breath, and heart failure are all possible signs of cardiac involvement [37, 38].

• Digestive involvement may result in digestive tract issues such as abdominal pain, constipation, and difficulties swallowing.

• Neurological symptoms such as seizures, muscle weakness, and sensory issues can be brought on by nervous system involvement [37, 38].

• Congenital transmission, or transmission from mother to foetus during pregnancy, is another side effect of Chagas disease. Infants with the infection may present with severe symptoms at birth or later in life [38, 39].

6. Laboratory diagnosis

6.1 Sleeping sickness (HAT)

Early diagnosis of sleeping sickness (HAT) is essential for effective treatment, but conventional procedures, such as blood smears and lymph node aspirates, can be time-consuming, intrusive, and unreliable.

The lack of specificity in the early signs and symptoms of the disease makes a diagnosis even more challenging. Therefore, establishing the parasite’s existence in any body fluid is necessary for the diagnosis. Parasitaemia levels in T. b. gambiense are often low and varied. Because of this, trypomastigotes are challenging to find in standard blood smears. By using light microscopy to find the parasite in a lymph node aspirate (often from a posterior cervical node), a T. b. gambiense infection is typically diagnosed. Blood can be concentrated using many methods, such as microhematocrit centrifugation, mini-anion exchange centrifugation, and centrifugation followed by buffy coat inspection. Symptomatic T. b. rhodesiense patients frequently have detectable parasites in their blood, and parasitemia is typically higher than it is with T. b. gambiense. Aspirates from bone marrow or chancre fluid may also contain the parasite [38, 39, 40].

6.2 Chagas illness

1. Serological tests: Serological testing, which looks for the presence of certain antibodies against Trypanosoma cruzi, is the most widely used technique for diagnosing Chagas disease. These tests include the indirect hemagglutination assay (IHA), the immunofluorescence assay (IFA), and the enzyme-linked immunosorbent assay (ELISA). Although very sensitive and specific, these tests are unable to distinguish between previous and present infections.

2. Microscopical analysis: In this method, parasites are specifically identified from a sample of blood, tissue, or fluids. It is helpful during the disease’s acute phase, when there are a lot of parasites. Due to the low parasite counts, it is an unreliable approach for identifying persistent infections. It is important to remember that a complete medical history and physical examination, together with an evaluation of the patient’s exposure to insect vectors in endemic areas, should be done before the diagnostic tests are carried out. Serological tests are frequently employed in the ongoing treatment of patients and are typically the first-line diagnostic tests [38, 39, 40].

6.3 Recent advances

Here are a few recent developments in trypanosomiasis diagnosis:

• RDTs (rapid diagnostic tests): One of the common methods used in the field for the first screening and diagnosis of T. b. gambiense HAT is the Card Agglutination Test for Trypanosomiasis (CATT). The CATT serodiagnostic test relies on the identification of anti-parasite antibodies in blood, plasma, or serum, whether the infection is acute or chronic. Despite being widely used and making a significant contribution to the control of HAT, the CATT test has a number of shortcomings. All of these elements prompted researchers to look for fresh serological techniques (such as tests based on antibodies or antigens). A number of rapid diagnostic tests (RDTs) for HAT have been created and released in the field recently in an effort to alleviate this predicament. Rapid diagnostic tests can find antibodies or antigens in the serum or blood of the infected person and are inexpensive, straightforward, and field-friendly. The lateral flow immunochromatographic assays (LFIAs), which are based on the detection of target analytes (in this case, antibodies) contained in a liquid sample (i.e., bodily fluids), are the most notable among the RDTs. These tests can deliver precise answers in under 30 min, making it simpler for medical professionals to diagnose the illness in far-off locations without the use of expensive laboratory apparatus. However, none of the antibody-based diagnostics are effective at determining whether an infection is present or past or at carrying out follow-up procedures after treatment. Ag-based tests, on the other hand, do remove this drawback and significantly enhance HAT diagnosis [40, 41, 42, 43]. These typically have reduced sensitivity (depending on the amount of antigens in the blood), but frequently exhibit significantly superior PPV (positive predictive value) as compared to Ab-based tests. Nevertheless, modern detection innovations like nanobodies can overcome this problem. Despite this, there is presently no Ag-test for HAT 43–46.

• Loop-mediated isothermal amplification (LAMP): An effective and sensitive molecular diagnostic method called LAMP makes it possible to detect Trypanosoma parasites in blood samples by rapidly amplifying DNA. Recent research has demonstrated the viability and precision of LAMP in the diagnosis of trypanosomiasis, with results that are even quicker than those from conventional tests like PCR (polymerase chain reaction). Its primary property is the isothermal nature of the reaction, which only needs a basic, inexpensive heat source (such as a portable heat block or a water bath) to maintain a single constant temperature. Similar to PCR, LAMP is a highly sensitive and specific method (mean values of 90 and 95%, respectively). Although its reaction time is quicker, it typically takes 60 min to produce the maximum amplification products, whereas only 30 min are needed to produce a visible signal [41, 42, 43, 44].

• PCR-based assays are used to identify Trypanosoma parasites in tissues, bodily fluids, and blood. Recent developments in PCR-based methods have improved their sensitivity, specificity, and usability. For instance, it has been demonstrated that real-time PCR amplification of conserved genes is sensitive and specific for the detection of Trypanosoma parasites in sick people. Due to its high cost, complexity, reaction time (about 1–2 h), need to regulate reaction temperatures (using a thermal cycler), need for specialised personnel, etc., PCR still does not have the status of a point-of-care (POC) test. Therefore, POC testing (i.e., active screening) cannot be done using this molecular-based technology; it is only appropriate for laboratory-based testing (i.e., passive screening) [45, 46, 47, 48, 49].

• RPA, or recombinase polymerase amplification: The isothermal approach known as recombinase polymerase amplification (RPA) is even more modern. RPA enables DNA amplification to be carried out at constant temperatures of 30–42°C, which is even lower than PCR and LAMP. This temperature is comparable to that of a healthy, typical adult human being. Therefore, the test’s incubation might be carried out while being held in the hand, under the arm, or another appropriately warm body part. Reaction times are about 20 min, which is an improvement over other molecular-based examination. While there isn’t yet an RPA test for HAT, there are RPA tests for Chagas disease that have 100% specificity and 93% sensitivity. Similar to LAMP, RPA can be carried out directly on blood samples even when there are potential biochemical inhibitors present, such as ethanol, heparin, or haemoglobin. RPA is currently only suitable for research-related applications because it has not yet received FDA approval [45, 46, 47, 48, 49].

• Nanopore sequencing: For quick pathogen detection and identification, nanopore sequencing is a real-time, portable sequencing method. Trypanosoma cruzi has been successfully detected using it [47, 48, 49].

• Use of mobile devices for microscopy: A mobile phone microscope (mScope) has been created using mobile phones that allows medical professionals to snap images of blood smears and microbeads that can identify the parasite protein. After that, the photos are sent to a central laboratory for analysis and diagnosis. This method has the potential to improve the sensitivity and specificity of microscopy, especially in distant locations with limited access to skilled workers and laboratory facilities [50, 51].

6.4 CRISPR-Cas

1. Functional genomics: CRISPR-Cas has been used to create knockout experiments that specifically target the Trypanosoma parasite genes that cause the disease. These techniques have made it possible to carry out gene-editing procedures that change the parasite’s DNA and stop its life cycle, revealing the genetic processes governing trypanosome gene expression, differentiation, and virulence [52, 53, 54].

2. Vector control: Tsetse flies are the main carriers of trypanosomiasis. It may be possible to stop the disease from spreading by genetically altering the tsetse’s capacity to propagate the parasite [54]. These insects have been modified by scientists to be resistant to Trypanosoma material, which will eventually lessen their influence on the spread of disease.

3. Gene editing: CRISPR-Cas has been used to precisely modify Trypanosoma parasite genes in addition to planning and carrying out knockout experiments. Because of the technology’s ability to modify the parasite’s DNA, treatment outcomes may be improved by reducing parasite resistance or maximising the impact of a medicine. Future improvements in the creation of extremely targeted therapeutic targets and pharmacological therapies may result from this [54, 55, 56].

4. Studying Trypanosoma multiplicity: Using CRISPR-Cas, scientists have found that populations of T. brucei contain a variety of genetic variants. The parasite’s antigenic presentation from the host’s immune system is covered by these variations, which are primarily in the VSG (Variant Surface Glycoprotein) coat, hindering detection and eradication. With the aid of this technology, researchers can create mutant Brucei strains with various surface coats that can be used to identify the genetic components responsible for the coat’s antigenic delivery [55, 56, 57].

Although CRISPR-Cas technology is still in its infancy, recent developments in the study of trypanosomiasis have shown significant promise for limiting the spread of Trypanosoma parasites. There is increased optimism that trypanosomiasis will one day be eradicated thanks to the creative uses of CRISPR-Cas technology in creating knockout trials, precision genomics, and vector control [56, 57].

Health professionals can now diagnose trypanosomiasis more quickly and easily, allowing them to diagnose the condition and cure patients. Although still in the early stages of development, these technologies have shown encouraging results and may be able to help stop the spread of trypanosomiasis in endemic areas.

7. Treatment

7.1 Treatment for sleeping sickness (HAT)

• Pentamidine and Suramin, which have a number of negative side effects, can be poisonous, and can eventually lose their effectiveness, have been used in traditional therapy methods. When the disease is in its second stage and has crossed the blood-brain barrier (BBB), melarsoprol is effective. Pentamidine and suramin are only efficient at reducing parasite infection during the first stage of sickness, when the parasitemia is only present in the blood and lymphatic system. This is because they cannot penetrate the BBB. However, administering melarsoprol is painful and extremely poisonous [58, 59]. The development of several novel pharmacological choices, however, has resulted in substantial advancements in the field of trypanosomiasis treatment, significantly enhancing patient results.

The following are some recent developments in the management of trypanosomiasis:

• Fexinidazole: The first oral medication ever authorised for the treatment of trypanosomiasis is fexinidazole. It is produced from the medication benzimidazole and works well to treat both the early and late phases of the illness. Fexinidazole, a medication authorised by the EMA, is currently being used to treat trypanosomiasis in endemic areas of Africa [58, 59].

• Combination therapy with nifurtimox and eflornithine (NECT): NECT is a cutting-edge technique of combination therapy that has demonstrated success in treating second-stage trypanosomiasis. By combining Nifurtimox and Eflornithine, two already-approved medications, the efficacy of the treatment is increased while the side effects of the individual medications are minimised [58, 59].

• A novel medication called acoziborole is effective against the parasite Trypanosoma, which causes the East African variant of sleeping sickness. It functions by preventing the creation of proteins by the parasites, denying them essential nutrition. It has a lot of potential as a new medication for the treatment of trypanosomiasis, especially in areas where older drug formulations are no longer working as well [59, 60].

Combination therapy and shorter treatment regimens: drug-resistant forms of the trypanosomiasis parasite have alarmingly increased. To maximise potency and prevent resistance, this has led to the creation of more effective combination medication therapy, including shorter course regimens like the 10-day NECT regimen, which improves patient compliance, leads to better treatment outcomes, and has a lower risk of adverse effects [61].

7.2 Recent clinically viable HAT candidates include

To improve accessibility and boost therapeutic efficacy, newly discovered medications should be less toxic than currently used treatments and acceptable for oral administration. Due to these restrictions, researchers are looking for alternative active compounds (such as those derived from nature) to treat HAT. Additionally, the pipeline of clinical prospects is quite small as a result of these restrictions. Fexinidazole is the most significant medication recently launched in therapy. Only two other candidates—parafuramidine and acoziborole—have profiles and results that are distinct from these two [62, 63].

7.3 Treatment for Chagas’ disease

Benznidazole and nifurtimox are the two major medications used to treat Chagas disease at the moment. Both medications work well to treat the acute stage of the illness, and early intervention can lessen the chance of developing a chronic condition. The recommended dosage for benznidazole is 5–7 mg/kg/day for adults and 5–10 mg/kg/day for children over the course of a 60-day course. The normal course of treatment for nifurtimox is a 90-day regimen that includes three doses each day of 15–20 mg/kg/day for adults and 10–15 mg/kg/day for children. Patients who have recent infections or infections in the acute phase often respond better to these therapy regimens [64].

Both benznidazole and nifurtimox have the potential to have negative side effects such as neurotoxicity, gastrointestinal problems, and skin sensitivities. Because they can seriously harm the unborn, certain medications should not be used by pregnant women. Patients with advanced chronic diseases may not respond well to treatment; in these situations, symptomatic or supportive care is given to help the patient feel better [64].

Recently, there hasn’t been much advancement in the treatment of Chagas disease, and the options that are currently available have a number of drawbacks, including toxicity, a long duration of treatment, high cost, and minimal efficacy against specific parasite strains. Here are some more recent developments in the management of Chagas disease, though:

• New medications in development: Clinical trials for several new medication candidates, including fexinidazole, benznidazole, and posaconazole, are now taking place at various stages. By considerably raising cure rates and cutting down on treatment time, these novel medications have demonstrated encouraging outcomes in preliminary clinical trials [65].

• Combination therapy: By focusing on several stages of the Trypanosoma cruzi parasite, the combination of two or more already-approved medications has the potential to increase the effectiveness of treatment. In fact, several studies have suggested that benznidazole and posaconazole together may be more effective than either drug used alone.

• Drug repurposing: Researchers are investigating novel therapeutic uses for drugs with other clinical indications that are not yet approved for the treatment of Chagas disease. These include certain angiotensin-converting enzyme inhibitors as well as medications like itraconazole and allopurinol [65].

In conclusion, there have been considerable improvements in the management of trypanosomiasis. There is new hope in the fight against trypanosomiasis thanks to the availability of novel oral medications, combination therapy, and vaccine candidates, along with shorter treatment schedules. The development of initiatives aiming at making a substantial effect that could result in the eradication of this lethal disease is being facilitated by ongoing research and development.

8. Prevention

8.1 Vaccines

• The VSG-based vaccine: The primary surface antigens of African trypanosomes are variant surface glycoproteins (VSGs), which frequently alter their antigenic makeup to thwart the host’s immunological response. In animal experiments, a VSG-based vaccination that targets the conserved portions of the protein has demonstrated encouraging outcomes. But it’s still in its infantile stages of growth.

• DNA vaccines: Clinical trials have been conducted on DNA vaccinations that utilise plasmids that encode Trypanosome surface antigens. These vaccinations have been used to safeguard animals against the Trypanosoma parasite with rather poor efficiency [66].

• Recombinant protein vaccines: To enhance the immune response to Trypanosome antigens, recombinant protein vaccines have been combined with DNA vaccinations. In animal experiments, a DNA vaccine and a recombinant protein vaccination against T. cruzi showed encouraging outcomes [67, 68].

• Passive immunisation: Monoclonal antibodies have been investigated for use in passive immunisation as a preventative and therapeutic measure for trypanosomiasis. Monoclonal antibodies directed against the VSG protein have demonstrated high efficiency in preventing infection in animal models when used as a passive immunisation [68, 69].

There is no medication available to prevent Chagas disease and African trypanosomiasis. The main goal of preventive measures is to reduce interaction with the fly population. In nations where these flies are endemic, locals are typically aware of the regions that are strongly infected and warn others about the situation. Other beneficial actions consist of: [70]

• Avoiding fly bites: By donning long-sleeved shirts and medium-weight, neutral-coloured clothing that blends in with the surroundings

• The motion and dust from driving cars attract flies. Therefore, it is best to check vehicles before entering.

• Avoiding shrubs is advisable. The tsetse fly will bite even if it is less active during the hottest part of the day.

• Making use of bug repellents.

9. WHO programmes for trypanosomiasis

9.1 WHO network for HAT elimination

To organise, support, and sustain efforts to eradicate HAT, WHO formed the “Network for HAT Elimination” [71]. This network connects all international organisations, research institutes, development agencies, nongovernmental organisations, and funders active in the control of HAT with all national sleeping sickness control programmes (NSSCPs) in Africa. Annual meetings of this network have been held in Yaoundé (March 2015), Geneva (March 2016), Conakry (2017, 2018), Geneva (April 2018), and Grand Bassam (February 2019).

By 2020, the World Health Organisation hoped to eradicate African trypanosomiasis as a public health issue. The ultimate objective of this plan will be the sustained eradication of illness by 2030, which is defined as the cessation of African trypanosomiasis transmission.

9.2 WHO response for Chagas’ disease

In 2005, the WHO designated Chagas’ illness as a neglected tropical disease (NTD) [72]. As a result, Chagas disease is now more widely acknowledged as a public health issue on a global scale. The creation of a World Chagas Sickness Day was approved by the 72nd World Health Assembly in May 2019 in order to increase public knowledge and awareness of what is frequently referred to as a “silent and silenced disease”. The first human instance of the disease, a 2-year-old girl named Berenice, was identified by Carlos Chagas on April 14, 1909; as a result, April 14 is recognised as World Chagas Disease Day.

The NTD road map includes five Chagas disease objectives:

1. verification of the interruption of vectoral domiciliary transmission

2. verification of interruption of transfusion transmission

3. verification of the interruption of transmission by organ transplants

4. elimination of congenital Chagas disease

5. 75% coverage of antiparasitic treatment for the eligible population

In order to achieve the goal of eradicating Chagas disease transmission, global networking will increase, and regional and national capacities will be strengthened. Additionally, to offer medical attention to those who are ill or sick with the disease in both endemic and non-endemic areas.

10. Conclusion

Two neglected tropical diseases, African Trypanosomiasis and Chagas disease, are caused by the parasites Trypanosoma brucei and Trypanosoma cruzi, respectively. Millions of individuals around the world are afflicted by these diseases, especially those who live in rural and underdeveloped areas. Both diseases have comparable methods of transmission, medical symptoms, and difficulties with treatment. There are currently few therapies available, and they frequently have serious negative effects.

Despite the obstacles, there has been substantial advancement in the creation of novel diagnostic techniques, therapies, and potential vaccinations for both diseases. The prevalence of these parasitic diseases has been shown to be reduced by preventive strategies such as vector control, disease surveillance, and education.

To achieve the global health objective of eradicating Chagas’ disease and African trypanosomiasis, interdisciplinary approaches including healthcare professionals, researchers, politicians, and impacted communities are essential.