Approach

The classical diagnosis of human African trypanosomiasis (HAT) is a three-step approach:

  • Identification of suspects

  • Parasitological confirmation

  • Disease staging

Identification of suspects is based on determining whether they have lived in or visited an endemic area, in combination with clinical signs and symptoms or with serological evidence (presence of trypanosome-specific antibodies in blood).

Parasite detection is considered as the confirmation of infection. It is relatively easy for T b rhodesiense, but often difficult with T b gambiense, where failure to demonstrate the parasite is not uncommon, even if concentration techniques are applied. For that reason, in some epidemiological situations, treatment decision is taken following serological and clinical evidence.[27]

Once parasites have been detected, the disease stage, in combination with the subspecies of causative trypanosome, determines the therapeutic choices for treatment.

History and clinical examination

Initial suspicion should be high in patients who have visited a HAT-endemic area in sub-Saharan Africa and present with a history of a tsetse bite, although the bite may go unnoticed.

Symptoms and signs are non-specific and variable and are, therefore, insufficient for diagnosis and staging. The onset of symptoms is usually more acute in individuals originating from non-endemic areas.[7][28]​ Patients often present with a history of malaria treatment without improvement.[29][30]

Symptoms and signs that may be seen in the first stage of disease include:

  • Fatigue

  • Headache

  • Fever

  • General malaise

  • Enlarged cervical lymph nodes (Winterbottom's sign; mainly T b gambiense)

  • Inoculation chancre (mainly T b rhodesiense)

  • Pruritus

  • Rash

  • Oedema

  • Hepatosplenomegaly

  • Endocrine dysfunctions (in women: history of infertility, amenorrhoea, and miscarriage; in men: reduced libido, impotence)

Patients with gambiense HAT progress from first to second stage after a mean time of 500 days.[31] In second-stage gambiense HAT, signs of first stage persist and signs of neurological involvement become apparent, including:[32]

  • Disturbances of consciousness and sleep (although this can also be present in first-stage disease)

  • Impaired motor functions (e.g., ataxia, disturbance of gait, tremors, abnormal movements)

  • Sensory disorders

  • Mental changes (e.g., inattention, disorientation in time and/or space, slowed thought processes, memory deficit)

  • Abnormal behaviour (e.g., disinhibition, excitement, euphoria, aggressiveness, indifference)

In patients with rhodesiense HAT, the duration of symptoms suggests that the disease progresses into second stage between 3 weeks and 2 months of infection.[33] Because of this acuteness, neurological involvement may remain absent. Patients are usually admitted presenting with multi-organ or cardiac failure with abnormal electrocardiogram results.[28][34]

Laboratory investigations

Although not sufficient to establish the diagnosis of HAT, common blood abnormalities include:[35][36]

  • Anaemia: mild for gambiense HAT, but severe in rhodesiense HAT

  • Thrombocytopenia: mild for gambiense HAT, may be severe in rhodesiense HAT

  • Moderate leukocytosis

  • Increased erythrocyte sedimentation rate (ESR)

  • Increased immunoglobulin (Ig) levels, especially IgM

Therefore, a full blood count, ESR, and serum immunoglobulins can be ordered to support the diagnosis.

The presence of a variety of non-specific antibodies has been reported during T b gambiense infection and consequently constitutes a risk for misdiagnosis, leaving HAT undetected.

Trypanosome-specific antibodies in blood are detectable by:

  • The card agglutination test for trypanosomiasis (CATT) for T b gambiense. This test is applied for screening of the population at risk in T b gambiense-endemic areas.

  • Enzyme-linked immunosorbent assay (ELISA) or immunofluorescence for T b gambiense and T b rhodesiense.

  • Rapid blood tests have been developed for detection of trypanosome-specific antibodies. They are an alternative to CATT and offer the advantage of being individual tests. They are, therefore, particularly suited for use in non-specialised centres that are occasionally confronted with T b gambiense HAT.[37][38][39][40]

Identification of a suspected case of HAT, based either on clinical findings or on serological tests, should be followed by microscopic examination for the presence of parasites:

  • The stained, thick drop examination on blood is the most commonly applied microscopic examination and allows differential diagnosis of malaria. The technique might remain negative in T b gambiense infections, which are characterised by low parasite levels in blood.

  • Blood concentration techniques, such as the microhaematocrit centrifugation technique, buffy coat technique, or mini-anion exchange centrifugation technique (mAECT), are indicated for detection of T b gambiense. Repetitive examinations might be needed for findings of T b gambiense. mAECT is considered the best test, with sensitivity around 75% to 85%.[41][42] Sensitivity of mAECT can be increased to between 91% and 96% when the buffy coat of larger volumes of blood is applied onto the column.[43][44]

  • It is generally accepted that cases of trypanosomiasis are defined by the microscopic demonstration of trypanosomes in any body fluid. Occasionally, cases of gambiense HAT have been defined serologically, such as the case of a patient living an endemic area who has a positive serology in CATT, using different titration thresholds.[27][45][46]

Other body fluids that can be examined microscopically for the presence of trypanosomes include:

  • Lymph node aspirate for T b gambiense

  • Chancre aspirate for T b rhodesiense

  • Cerebrospinal fluid (CSF)

Disease staging

Once the infection has been confirmed, or in the case of a high index of suspicion for infection (such as an elevated CATT and titre and/or neurological symptoms), a lumbar puncture should be performed and the CSF examined for disease staging to help guide treatment.[32]

Patients who can be managed without lumbar puncture

  • Patients ≥6 years of age and body weight ≥20 kg who meet both of the following conditions:

    • Low index of suspicion of severe disease based on clinical judgement; and

    • High confidence that the patient will have appropriate follow-up to detect relapse early.

  • These patients do not require staging and may be treated preferentially with fexinidazole.

Patients who require lumbar puncture

  • Patients who do not meet the above criteria

  • Patients who reject or do not tolerate fexinidazole

If lumbar puncture and CSF examination is required, disease staging for gambiense and rhodesiense HAT is as follows:[32]

  • First-stage disease (also called early stage or haemolymphatic stage):

    • ≤5 white blood cells (WBC)/microlitre AND no trypanosomes in the CSF

  • Second-stage disease (also called late stage or meningoencephalitic stage):

    • >5 WBC/microlitre OR trypanosomes in the CSF

The second stage of gambiense HAT can be further classified as severe.

  • Severe second-stage disease (also called severe meningoencephalitic stage): ≥100 WBC/microlitre in the CSF with or without trypanosomes.

Emerging investigations

Although brain MRI has no role in diagnosis of HAT, meningeal thickening and bilateral confluent hyperintensive T2 signal of supratentorial white matter, brainstem, and cerebellum may be seen. Abnormalities remain present after successful cure.[47][48]

Immune trypanolysis is an emerging test in which live T b gambiense trypanosomes are incubated with human serum or plasma.[49][50]​ The specificity of immune trypanolysis is considered to be 100%, and a positive immune trypanolysis appears to be an indicator for contact with T b gambiense. The test can be performed only in highly specialised laboratories.

Various CSF proteins and markers of cellular immune system activation, as well as detection of RNA, are being investigated as markers for staging and treatment outcome assessment.[51][52][53][54][55][56]​​​

Use of this content is subject to our disclaimer