SLEEPING SICKNESS: SYMPTOMS AND ADVANCES IN TREATMENT

Sleeping sickness is a parasite-based illness transmitted through the bite of the tsetse fly. The scientific name for sleeping sickness is Human African trypanosomiasis (HAT). The parasite Trypanosoma brucei that causes this disease is prevalent in sub-Saharan Africa.

Sleeping sickness has a significant impact on the affected communities, with an estimated 65 million people at risk of infection. It also has a significant economic impact, as it affects individuals in their most productive years and can lead to long-term disability.

Older treatment options displayed limited effectiveness, sometimes contributing to worse outcomes. Ongoing research attempts to enhance diagnosis and treatment, with recent breakthroughs dramatically improving the lives of those affected. Recent research advances inspire hope for the eradication of this devastating illness.

This article explores the development, symptoms, and new advances in the fight against sleeping sickness.

Sleeping Sickness Transmission

The tsetse fly is endemic to rural areas of sub-Saharan Africa and feeds on the blood of humans and animals. When a tsetse fly carrying parasites bites, the parasite infiltrates the bloodstream and multiplies, leading to symptoms and complications.

African trypanosomes, known as Old World trypanosomes, are protozoan hemoflagellates belonging to the subgenus Trypanozoon. They cause distinct human diseases collectively known as sleeping sickness, as illustrated below:

• T. b. gambiense causes chronic African trypanosomiasis, also known as West African sleeping sickness.
• T. b. rhodesiense causes acute African trypanosomiasis, also known as East African sleeping sickness.
• Recently, scientists have discovered that T. b. brucei might infect people. When this happens, the infection causes hemoglobin to be released from red blood cells. Due to its ability to attach to a tiny portion of high density lipoprotein, or "good cholesterol," hemoglobin appears to "arm" the human innate immune system. Trypanosomes are then eliminated from the body by the human innate immune system with the help of the hemoglobin-HDL complex, which acts as a super toxin.^[1]

Symptoms of Sleeping Sickness

HAT symptoms vary depending on the stage of the disease.^[2]

There are two disease stages: early-stage (hemolymphatic) and late-stage (meningoencephalitic). They are sometimes known as acute sleeping sickness and chronic sleeping sickness.

Early-stage (hemolymphatic) sleeping sickness

• The parasite multiplies in the bloodstream and lymph nodes.
• Symptoms include fever, headache, rash, fatigue, and lymphadenopathy (swollen lymph nodes).
• Symptoms are easily mistaken for other illnesses, challenging early diagnosis.
• The parasite is transmissible to other people through blood transfusion or contact with infected bodily fluids.

Late-stage (meningoencephalitic) sleeping sickness

• The parasite traverses the blood-brain barrier and overruns the central nerves of the brain and spinal column.
• Progression to late-stage illness can take three weeks to eighteen months, depending on the parasite responsible.^[3]
• Symptoms include sleep disturbances, confusion, tremors, coma, seizures, and other neurological problems.
• The disease is usually fatal if left untreated.
• If treated, late-stage sleeping sickness may result in lifelong neurological complications.

The physiological development of sleeping sickness is complex and not fully understood. Evidence suggests that the parasite evades the immune system by changing its surface proteins. This evasion allows the parasite to multiply and spread throughout the body.

In the late stage of the disease, the parasite invades the CNS, where it can cause severe neurological symptoms and damage.

Prognosis

The prognosis for sleeping sickness depends on the disease's stage and the treatment's effectiveness. In the acute stage, the disease is curable with treatment, but if left untreated, it can be fatal. In the chronic stage, treatment can improve symptoms, but long-term neurological complications may persist. Recent breakthroughs allude to a complete cure for the chronic phase as well.

Diagnosis of Sleeping Sickness

Diagnosing sleeping sickness can be challenging, as the early symptoms are non-specific and can be mistaken for other illnesses. Diagnostic methods include:

• Blood tests: A blood sample is taken and examined under a microscope to look for the parasite.
• Lumbar puncture: A cerebrospinal fluid sample is necessary to check for the presence of the parasite.
• Serological tests: These tests look for antibodies produced by the body in response to the parasite.

Treatment of Sleeping Sickness

The treatment for sleeping sickness depends on the type and stage of the disease.^[4]

In the acute stage, the following treatments are standard:

• Gambiense-HAT: Pentamidine as an intramuscular injection. Therapy is usually tolerable with few side effects.
• Rhodesiense-HAT: Suramin administered by IV. It may trigger adverse reactions such as kidney toxicity and allergies.

In the chronic stage, treatment consists of:

• Gambiense-HAT: Eflornithine-Nifurtimox combination therapy, often co-administered intravenously. Combination therapy reduces the amount of treatments necessary. It requires hospitalization and is expensive.
• Rhodesiense-HAT: Intravenous Melarsoprol therapy. As an arsenic derivative, Melarsoprol is a dangerous treatment option. Reactive encephalopathy is the worst side effect, with a mortality rate of 3-10%.

Continuous post-treatment monitoring is also vital for managing symptoms and preventing potential relapse, especially during the chronic phase. Additionally, treatment-related adverse effects require close surveillance and supportive care.

New Advances in the Fight Against Sleeping Sickness

Recently, a new drug called fexinidazole was approved to treat sleeping sickness caused by the gambiense parasite. It is a revolutionary oral treatment for acute sleeping sickness that combats the disease's acute and chronic stages. This drug has demonstrated favorable outcomes in clinical trials, is capable of curing up to 97% of cases, and is expected to have a significant impact on the treatment of sleeping sickness.^[5]

Another drug to soon follow fexinidazole’s footsteps is acoziborole. Acoziborole passed phase II/III clinical trials in 2022. The trial included 208 patients with sleeping sickness and found that acoziborole was 95.2% effective in curing late-stage disease and 98.1% effective in curing the disease overall. The drug was also well-tolerated, with most side effects being mild or moderate.^[6]

New tests for T. b. gambiense infection have been created and are now used in countries where the disease is common. These tests, called HAT Sero-K-SeT and SD Bioline HAT 1.0, are easier to use in places without electricity or labs. These tests help with disease control and surveillance in health centers.^[7]

Future Directions

Ongoing research attempts to refine the diagnosis and treatment of sleeping sickness.

Focus areas include:

• Developing new diagnostic tools for early parasite detection and improving treatment outcomes.
• Research into new drugs that are more effective and have fewer side effects, enhances patient quality of life and accessibility to treatment.
• Adequate training and education to improve the quality of treatment in endemic areas.

Gene therapies are a promising approach for tackling sleeping sickness.

One example of a promising preclinical gene therapy works by attacking the ribosome of the trypanosome parasite. The ribosome is responsible for producing proteins in the parasite, and by damaging the ribosome, the drug can prevent the parasite from growing and causing disease. Researchers discovered that the parasite’s ribosome is different from the ribosomes of humans and other mammals, meaning that the drug will not harm humans or other mammals while defeating the parasite.^[8]

Another promising avenue for treatment is antibody-drug conjugates (ADCs).

ADCs are a type of drug that combines a monoclonal antibody with a cytotoxic drug. The antibody targets a specific molecule on the parasite's surface, while the drug kills the parasite.

In a preclinical study, researchers created an ADC that targets the trypanosome haptoglobin-hemoglobin receptor (HpHbR). This receptor is on the surface of all trypanosomes, including the ones that cause sleeping sickness. The ADC delivers a pyrrolobenzodiazepine (PBD) toxin to the parasite. This toxin destroys trypanosomes explicitly and does not harm human cells.

The ADC was able to cure a stage 1 mouse model of trypanosomiasis with a single dose. This result significantly improves over current treatments, which require multiple doses and can have severe side effects. Researchers believe this ADC may be the next safe and effective treatment for sleeping sickness in humans.

Disease Control and Prevention

In addition to bettering current diagnosis and treatment options, efforts are also being made to control and prevent the spread of sleeping sickness. Prevention measures include vector control, which involves targeting and eliminating the tsetse fly population in affected areas.

Community education is also crucial in preventing the spread of sleeping sickness. By educating communities on the symptoms and transmission of the disease, individuals can take steps to protect themselves and seek treatment if necessary.

Conclusion

Sleeping sickness, also known as Human African trypanosomiasis, is a parasitic condition transmitted through the bite of the tsetse fly. It significantly impacts the affected communities and requires ongoing research to improve diagnosis and treatment. New advances, such as fexinidazole, show promise in the fight against sleeping sickness. With continued efforts in disease control, prevention, and research, we can work towards eliminating this disease and improving the lives of those affected.

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