African Sleeping Sickness

Human African Trypanosomiasis (HAT) is a life-threatening neglected tropical disease caused by protozoan parasites Trypanosoma brucei gambiense (West/Central Africa, ~95% of cases, chronic) and T. b. rhodesiense (East/Southern Africa, ~5%, acute), transmitted by the tsetse fly (Glossina spp). Fatal if untreated. [1-2]

The following figure illustrates the life cycle of the parasite through the tsetse fly vector and human host, highlighting the diagnostic implications at each stage:

• Travel history is paramount: recent or remote travel to sub-Saharan Africa, specifically rural/forested areas with tsetse fly exposure [2][4]
• Activities increasing exposure: farming, water collection, hunting, fishing, wood gathering [5]
• Symptom timeline: gambiense incubation can be months with a mean disease duration ~3 years; rhodesiense incubation is days to 3 weeks with rapid progression [1]
• Ask about: intermittent fevers, persistent headache, pruritus, arthralgias, weight loss, fatigue, malaise, sleep disturbances (daytime somnolence, nocturnal insomnia) [1][6]
• Painful skin lesion at bite site (trypanosomal chancre) — more common in rhodesiense (5–26% in endemic populations, up to 88% in travelers) [1]
• Important negatives: no response to antimalarials (recurrent fever despite treatment is a key clue), no typical malaria periodicity [7]

• Neurological signs indicating severe second-stage disease: mental confusion, atypical behavior, logorrhoea, anxiety, ataxia, tremor, motor weakness, speech impairment, irregular gait, abnormal movements, seizures [1][8]
• Rhodesiense-specific red flags: hemodynamic instability, signs of myocarditis/pericarditis, congestive heart failure, multiorgan failure — patients can die of cardiac failure before neurological manifestation [1][9]
• Progressive somnolence, coma, incontinence, cachexia [1]
• Rapid clinical deterioration (rhodesiense can be fatal within days to weeks) [1]

Six drugs are currently available (all donated by manufacturers and distributed free via WHO): [1]

• Fexinidazole (oral, 10-day course): Now first-line for both gambiense and rhodesiense HAT in patients ≥6 years and ≥20 kg. Must be taken with a substantial meal for adequate absorption. Loading dose × 4 days, then maintenance × 6 days [1-2][8]
  • QT prolongation[1-2]
• Pentamidine (IM, 7 days): First-line for first-stage gambiense HAT in children <6 years or <20 kg; bridge therapy for rhodesiense when fexinidazole unavailable. Caution: severe hypotension, hypoglycemia [1][8]
• NECT (nifurtimox PO + eflornithine IV): For severe second-stage gambiense HAT (CSF WBC ≥100/μL). Eflornithine requires IV infusion × 7 days [1][8]
• Suramin (IV, weekly × 5 weeks): First-stage rhodesiense in children <6 years/<20 kg. Test dose required (anaphylaxis risk). Nephrotoxic [1]
• Melarsoprol (IV): Reserved for second-stage rhodesiense in children <6 years/<20 kg or when fexinidazole cannot be given. Encephalopathic syndrome in ~7%, treatment-related death in 3–8% [1-2]
• Contraindicated medications: Melarsoprol is no longer recommended for gambiense HAT due to unacceptable toxicity [10]

• Fexinidazole must be taken with food — bioavailability is substantially compromised in the fasting state, which can lead to treatment failure [1][8]
• Nutritional support is critical in advanced disease with cachexia
• Adequate hydration, especially with vomiting from fexinidazole (reported in ~38% of patients) [2]

• Constitutional: Intermittent fever, weight loss, fatigue, malaise, night sweats [1][6]
• Neurological: Sleep-wake cycle disruption, daytime somnolence, headache, tremor, gait disturbance, confusion, behavioral changes, seizures [1][6]
• Dermatologic: Chancre at bite site, circinate/serpentine rash, generalized pruritus, facial edema [1]
• Cardiovascular: Chest pain, dyspnea, palpitations (myocarditis/pericarditis) [1][6]
• Lymphatic: Painless lymphadenopathy, especially posterior cervical [1]
• GI: Hepatosplenomegaly, diarrhea (especially in travelers) [6]
• Endocrine: Amenorrhea, impotence, alopecia [1][6]
• Psychiatric: Hallucinations, anxiety, irritability, excessive sexual impulses, behavioral disturbances [6]

• Detailed travel itinerary to sub-Saharan Africa — specific countries, rural vs. urban, duration, activities [2][6]
• Occupation and outdoor exposure in endemic areas
• Prior tsetse fly bites or known exposure
• Family members or travel companions with similar symptoms
• No hereditary predisposition; HAT is entirely vector-borne
• In non-endemic settings, travelers and expatriates present atypically with acute febrile illness regardless of subspecies [6]

• Travel to or residence in tsetse fly–endemic areas of sub-Saharan Africa [2]
• Rural exposure: farming, fishing, hunting, water collection in forested/riverine areas [5]
• Gambiense: West/Central Africa (DRC accounts for >80% of cases) [4]
• Rhodesiense: East/Southern Africa (Uganda, Malawi, Tanzania, Zambia) [2]
• Safari travelers, aid workers, researchers in endemic zones
• No vaccine or chemoprophylaxis available
• Lack of personal protective measures against tsetse flies

• Malaria — most common misdiagnosis; intermittent fever, similar geography. Key distinguisher: HAT fever does not respond to antimalarials [1][7]
• HIV infection — lymphadenopathy, weight loss, neuropsychiatric symptoms [6]
• Tuberculosis — chronic fever, weight loss, lymphadenopathy [6]
• Typhoid fever — prolonged fever, hepatosplenomegaly [6]
• Viral encephalitis — CNS involvement, altered mental status [6]
• Brucellosis — undulant fever, arthralgias [6]
• Leishmaniasis — hepatosplenomegaly, fever, pancytopenia [6]
• Toxoplasmosis — CNS involvement in immunocompromised [6]
• Lymphoma — generalized lymphadenopathy, constitutional symptoms
• Chancre may mimic arachnid/insect bites or eschar (e.g., rickettsial disease) [1]

• Previous episodes of HAT (relapses can occur)
• Prior treatment with HAT drugs (risk of drug resistance, cross-resistance between nifurtimox and fexinidazole) [1][8]
• HIV status (co-infection complicates management)
• Cardiac history (relevant given myocarditis risk and QT-prolonging drugs)
• Renal function (suramin is nephrotoxic) [1]
• Hepatic function (drug metabolism considerations)
• Psychiatric history (fexinidazole neuropsychiatric adverse effects) [1]

• Vital signs: Intermittent fever (irregular pattern), tachycardia, hypotension (cardiac involvement in rhodesiense) [1]
• Winterbottom's sign: Painless, soft, enlarged posterior cervical lymph nodes — classic for gambiense HAT [1][9]
• Trypanosomal chancre: Painful erythematous lesion 2–5 cm at bite site, no necrosis, larger than typical eschar [1]
• Trypanosomal rash: Circular or serpentine outline, transient, migratory [1]
• Hepatosplenomegaly [1]
• Facial/peripheral edema [1]
• Neurological exam: Assess for tremor, ataxia, motor weakness, abnormal gait, speech impairment, abnormal movements, altered mental status, seizures [1][8]
• Kerandel's sign: Delayed hyperaesthesia at bone crests or soft tissues [1]
• Cardiac exam: Signs of pericardial effusion, heart failure (especially rhodesiense) [1][9]

• Giemsa-stained thick and thin blood films — gold standard for rhodesiense (high parasitemia); may require repeated exams and concentration techniques for gambiense [1][11]
• Buffy coat preparation — concentrates trypanosomes; ~50% sensitivity for gambiense [1]
• Mini anion exchange centrifugation technique (mAECT) — ~80% sensitivity for gambiense [1]
• Lymph node aspirate microscopy — when palpable cervical nodes present [1]
• Serological screening (gambiense only): CATT or lateral flow RDTs (HAT Sero K-SeT: 100% sensitivity, ~94% specificity) [1][7]
• CSF analysis for staging: WBC count and trypanosome detection
  • Stage 1: ≤5 WBC/μL, no trypanosomes in CSF [1]
  • Stage 2: >5 WBC/μL or trypanosomes in CSF [1]
  • Severe stage 2: ≥100 WBC/μL (requires NECT over fexinidazole for gambiense) [1][8]
• CBC: Anemia, thrombocytopenia, leukocytosis
• CMP: Renal function (baseline before suramin), hepatic function
• ECG monitoring during fexinidazole treatment (QT prolongation) [1-2]
• PCR available through CDC/reference labs (sensitivity ~99%, specificity ~98%) but not widely available in field settings [6]

• No specific imaging is diagnostic for HAT
• Echocardiography: Indicated in rhodesiense HAT to evaluate for myocarditis, pericardial effusion, cardiac dysfunction [1][9]
• Brain MRI: May show white matter changes or meningoencephalitic features in second-stage disease, but not routinely required for diagnosis or staging
• Chest X-ray: If pulmonary edema or pericardial effusion suspected
• Imaging is generally unnecessary for diagnosis — staging relies on CSF examination [1]

• Lumbar puncture with CSF examination: The critical staging test. Required for children <6 years/<20 kg, and when clinical signs suggest severe second-stage disease. Can be avoided in adults/older children without neurological signs when fexinidazole is planned [1][8]
• CATT (Card Agglutination Test for Trypanosomiasis): Serological screening for gambiense; titer ≥1:16 considered positive [1][6]
• Lateral flow RDTs: Individual screening for gambiense in field settings [1]
• Trypanolysis test: Specific for T. b. gambiense contact; reference lab only [1]
• Indirect ELISA–T. b. gambiense: ~99% specificity, available for high-throughput screening [1]
• Chancre aspirate: Can detect trypanosomes within days of rhodesiense infection [1]

• Baseline ECG recommended before fexinidazole initiation — QT prolongation is a recognized adverse effect [1-2]
• Monitor for QTc prolongation during treatment course
• In rhodesiense HAT: ECG may show signs of myocarditis (ST-T wave changes, arrhythmias, conduction abnormalities) or pericarditis [1][6]
• Avoid concurrent QT-prolonging medications during fexinidazole therapy

• HAT is a two-stage disease: haemolymphatic (stage 1) → meningoencephalitic (stage 2) [1]
• Gambiense HAT: Chronic, insidious course over months to years; often misdiagnosed as malaria. Winterbottom's sign is classic. Spontaneous cure or chronic carriage has been rarely observed [1]
• Rhodesiense HAT: Acute, rapidly progressive over days to weeks; can present as severe sepsis with cardiac involvement and multiorgan failure before neurological signs appear [1]
• Travelers present atypically: acute febrile illness regardless of subspecies, chancre more common (88%), diarrhea and jaundice may lead to erroneous GI diagnosis, sleep disturbances and lymphadenopathy less common [6]
• Complications: reactive encephalopathy (especially with melarsoprol), irreversible neurocognitive impairment, cardiac failure, superimposed bacterial infections, cachexia, death [1-2]

Initial stabilization (especially rhodesiense)

• IV access, hemodynamic monitoring, treat concurrent malaria if present
• Rhodesiense HAT must be treated without delay — can progress to multiorgan failure rapidly [1]

Definitive treatment by subspecies and stage: [1-2]

Key treatment pearls

• Fexinidazole: must be taken with food; directly observed therapy for all 10 days [1][8]
• Monitor for neuropsychiatric adverse effects and QT prolongation during fexinidazole [1-2]
• Suramin: test dose required before full treatment (anaphylaxis risk); monitor renal function [1]
• In non-endemic countries, contact the CDC for drug access and specialist consultation — WHO maintains strategic emergency drug depots [2][11]
• Acoziborole (single oral dose) is a promising pipeline drug for gambiense HAT, with phase 2/3 data showing efficacy in both stages [12]

• All confirmed HAT cases require admission for treatment initiation, monitoring, and staging [1-2]
• Fexinidazole requires 10 days of directly observed therapy with food, ideally in a health facility [8]
• NECT requires hospitalization for IV eflornithine infusions [8]
• Rhodesiense HAT: ICU-level care may be needed for hemodynamic instability, cardiac involvement, or multiorgan failure [1]
• Infectious disease consultation is essential, especially in non-endemic settings
• Contact CDC Parasitic Diseases Hotline (in the US) for drug access and management guidance [11]

Post-treatment follow-up: [1-2][8]

• Gambiense HAT (fexinidazole): Clinical assessment at 6, 12, 18, and 24 months post-treatment, or at any time if symptoms recur
• Rhodesiense HAT (fexinidazole): Clinical evaluation at end of treatment, 1, 3, 6, and 12 months post-treatment
• Pentamidine/NECT: Systematic follow-up currently not routinely recommended but clinical vigilance maintained [8]

Return precautions — seek immediate care for

• Recurrence of fever, headache, or sleep disturbances
• Any new neurological or psychiatric symptoms (confusion, tremor, gait changes, seizures)
• Signs of cardiac decompensation

Key counseling points

• Relapses with fexinidazole can occur up to 12–24 months after treatment [8]
• Drug resistance is a theoretical concern (cross-resistance between nifurtimox and fexinidazole) [1][8]
• Treatment success defined as: alive, no trypanosomes in any body fluid, CSF WBC normalizing by 6 months [2]
• No vaccine or chemoprophylaxis exists — prevention relies on tsetse fly avoidance (long sleeves, neutral-colored clothing, insect repellent, avoiding bushland during peak biting hours) [2]

1. Human African Trypanosomiasis. — Lejon V, Lindner AK, Franco JR. Lancet. 2025.

2. New WHO Guidelines for Treating Rhodesiense Human African Trypanosomiasis: Expanded Indications for Fexinidazole and Pentamidine. — Lindner AK, Lejon V, Barrett MP, et al. The Lancet. Infectious Diseases. 2025.

3. Overview of the Diagnostic Methods Used in the Field for Human African Trypanosomiasis: What Could Change in the Next Years?. — Bonnet J, Boudot C, Courtioux B. BioMed Research International. 2015.

4. Oral Fexinidazole for Late-Stage African Trypanosoma Brucei Gambiense Trypanosomiasis: A Pivotal Multicentre, Randomised, Non-Inferiority Trial. — Mesu VKBK, Kalonji WM, Bardonneau C, et al. Lancet. 2018.

5. Chemotherapy for Second-Stage Human African Trypanosomiasis: Drugs in Use. — Lutje V, Probyn K, Seixas J, Bergman H, Villanueva G. The Cochrane Database of Systematic Reviews. 2021.

6. Clinical Features, Diagnosis, and Treatment of Human African Trypanosomiasis (Sleeping Sickness). — Kennedy PG. The Lancet. Neurology. 2013.

7. Passive Surveillance of Human African Trypanosomiasis in the Democratic Republic of the Congo: Clinical Presentation and Prospective Evaluation of Rapid Diagnostic and Reference Laboratory Test Accuracy. — Makabuza J, Lukusa IN, Lumbala C, et al. PLoS Neglected Tropical Diseases. 2025.

8. New WHO Guidelines for Treatment of Gambiense Human African Trypanosomiasis Including Fexinidazole: Substantial Changes for Clinical Practice. — Lindner AK, Lejon V, Chappuis F, et al. The Lancet. Infectious Diseases. 2020.

9. The Trypanosomiases. — Barrett MP, Burchmore RJ, Stich A, et al. Lancet. 2003.

10. Recent Progress in Diagnosis and Treatment of Human African Trypanosomiasis Has Made the Elimination of This Disease a Realistic Target by 2030. — Álvarez-Rodríguez A, Jin BK, Radwanska M, Magez S. Frontiers in Medicine. 2022.

11. Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2024 Update by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM). — Miller JM, Binnicker MJ, Campbell S, et al. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America. 2024.

12. Efficacy and Safety of Acoziborole in Patients With Human African Trypanosomiasis Caused by Trypanosoma Brucei Gambiense: A Multicentre, Open-Label, Single-Arm, Phase 2/­3 Trial. — Betu Kumeso VK, Kalonji WM, Rembry S, et al. The Lancet. Infectious Diseases. 2023.