Clinical management of East African trypanosomiasis in South Africa: Lessons learned Express News
These frequently start with evacuation logistics. The need for urgent treatment, given the progressive and multisystem nature of EAT, is often unrecognized, leading to delays in referral for definitive treatment. Apart from administrative delays in arranging air ambulance transport, sometimes because insurance companies resist authorizing evacuation on the grounds of an incorrect diagnosis or erroneous assessment of the clinical severity (e.g., cases 13 and 21), there may be further obstacles because of the clinical condition of the patient. They are frequently very ill and may be bleeding, and therefore viral haemorrhagic fevers (VHFs) are often part of the differential diagnosis (case 20). The labelling of a patient as having VHF, even if only speculative, frequently leads to suboptimal assessment and management by nervous medical, nursing, and transport personnel, and special permission may be required from port health authorities for the aircraft to land in South Africa, contributing to further delays in the evacuation process.
The lack of accurate information about the date of symptom onset (patients were sometimes too ill to provide accurate histories) precluded the quantitation of delays in diagnosis, which have been described by others (Sinha et al., 1999xSinha et al., 1999Sinha, A., Grace, C., Alston, W.K., Westenfeld, F., and Maguire, J.H. African trypanosomiasis in two travelers from the United States. Clin Infect Dis. 1999;
Google ScholarSee all References, Spencer et al., 1975xSpencer et al., 1975Spencer, H.C. Jr., Gibson, J.J. Jr., Brodsky, R.E., and Schultz, M.G. Imported African trypanosomiasis in the United States. Ann Intern Med. 1975;
Google ScholarSee all References). Simarro et al. (2011)xSimarro et al., 2011Simarro, P.P., Diarra, A., Ruiz Postigo, J.A., Franco, J.R., and Jannin, J.G. The human African trypanosomiasis control and surveillance programme of the World Health Organization 2000-2009: the way forward. PLoS Negl Trop Dis. 2011;
Google ScholarSee all References)Simarro et al. (2011) noted delays in diagnosis of between 1 and 7 days after admission in 17 of the 68 cases listed.
Local access to treatment has substantially improved with the help of the WHO, as described above. Both suramin and melarsoprol are potentially toxic and need to be administered carefully, and the National Institute for Communicable Diseases is able to advise clinicians on dosage and the management of side effects. The process of giving suramin to clear the blood of trypanosomes before lumbar puncture for CSF tests is not always followed. Clinicians are often anxious to investigate possible CNS involvement. While the risk of introducing trypanosomes into the CSF is regarded as largely theoretical (Pépin and Donelson, 2006xPépin and Donelson, 2006Pépin, J. and Donelson, J.E. in: R.L. Guerrant, D.H. Walker, P.F. Weller
African trypanosomiasis (sleeping sickness). Tropical infectious diseases. 2nd ed. Elsevier,
Google ScholarSee all ReferencesPépin and Donelson, 2006), it is important to avoid possible false-positive CSF findings from a ‘bloody tap’ if there are still trypanosomes in the bloodstream (Sinha et al., 1999xSinha et al., 1999Sinha, A., Grace, C., Alston, W.K., Westenfeld, F., and Maguire, J.H. African trypanosomiasis in two travelers from the United States. Clin Infect Dis. 1999;
Google ScholarSee all ReferencesSinha et al., 1999), which might lead to a decision to use the more toxic melarsoprol for therapy. Although some of the case patients did have premature lumbar punctures, fortunately none consequently developed CNS trypanosomiasis.
Patients with severe trypanosomiasis frequently have multi-organ involvement, as noted by Büscher et al. (2017)xBüscher et al., 2017Büscher, P., Cecchi, G., Jamonneau, V., and Priotto, G. Human African trypanosomiasis. Lancet. 2017;
Google ScholarSee all References)Büscher et al. (2017) and others, and require high levels of clinical care, sometimes including haemodialysis and mechanical ventilation (cases 19 and 20), and access to diagnostic laboratories, to survive. Cases in Johannesburg were generally managed in intensive care units, but in countries where the infection is acquired, or in smaller centres where patients may first present with illness, sophisticated facilities may not be available. Common complications that need to be looked for, and treated correctly, include myocarditis, fluid overload (contributing to the development of acute respiratory distress syndrome), thrombocytopenia, disseminated intravascular coagulopathy and bleeding, and hepatic and renal failure, which may all precede CNS invasion. Table 2Table 2 summarizes some of the laboratory findings in this EAT series, showing the typical abnormalities of bone marrow, renal, and hepatic function.
|Laboratory investigation||Average value (range)||Reference value or range||No. of case records|
|Haemoglobin||12.8 (9.9–15.1) g/dl||14.3–18.3 g/dl||9|
|Leukocyte count||6.0 (0.77–16.93) × 109/l||3.9–9.9 × 109/l||10|
|Platelet count||27.2 (5–79) × 109/l||150–450 × 109/l||15|
|Aspartate aminotransferase (AST)||310 (132–696) U/l||<38 U/l||10|
|Alanine aminotransferase (ALT)||351 (95–943) U/l||<50 U/l||10|
|Gamma glutamyltransferase (γGT)||330 (45–493) U/l||<60 U/l||5|
|Alkaline phosphatase (ALP)||304 (101–407) U/l||40–130 U/l||4|
|Bilirubin (total)||213 (72–511) μmol/l||5–21 μmol/l||8|
|Bilirubin (conjugated)||147 (97–248) μmol/l||0–5 μmol/l||5|
|Urea||17.1 (5.4–49.3) mmol/l||<8.4 mmol/l||7|
|Creatinine||241 (61–790) μmol/l||64–104 μmol/l||8|
|C-reactive protein (CRP)||187 (121–376) mg/l||<5 mg/l||6|
|Procalcitonin||2.9 (0.41–5.53) ng/ml||0–0.05 ng/ml||4|
Clinical signs of CNS pathology are not sensitive or specific predictors of CNS invasion (MacLean et al., 2012xMacLean et al., 2012MacLean, L., Reiber, H., Kennedy, P.G., and Sternberg, J.M. Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response. PLoS Negl Trop Dis. 2012;
Google ScholarSee all ReferencesMacLean et al., 2012). A depressed mental state may accompany metabolic derangements associated with infection, and conversely a patient without clinical evidence of CNS involvement may have CSF evidence of invasion. Therefore, empiric treatment must never be based purely on clinical findings, and every patient, irrespective of clinical condition, must have an examination of CSF once the peripheral blood smear is clear of parasites. Table 3Table 3 shows the CSF laboratory results that were available for this case series. Both of the patients who required melarsoprol had CSF lymphocyte counts >80 × 106/l; the highest CSF leukocyte count in the other patients was 15 × 106 neutrophils/l, but protein levels varied widely.
|Case number||Cell count ( × 106/l)
(Normal range, lymphocytes 0–5)
(Normal range 0.15–0.45)
|4||Lymphocytes: 1||Not reported||No|
|17||White blood cells: 7||Not reported||No|
In the laboratory diagnosis of CNS invasion, finding trypanosomes in the CSF is definitive if the bloodstream infection has been cleared. The interpretation of CSF chemistry and cytology alone is more difficult if only subtle changes are present, and strict application of arbitrary thresholds for lymphocyte and (particularly) protein levels in the CSF (e.g. >5 × 106 lymphocytes/l and 0.25 to 0.45 g/l protein, depending on local laboratory reference values) (Büscher and Lejon, 2004xBüscher and Lejon, 2004Büscher, P. and Lejon, V. Diagnosis of human African trypanosomiasis. in: I. Maudlin, P.H. Holmes, M.A. Miles
The Trypanosomiases. CABI Publishing,
Google ScholarSee all ReferencesBüscher and Lejon, 2004) without taking the clinical picture into account, may lead to overdiagnosis of CNS involvement and unnecessary use of the toxic agent melarsoprol. These comments apply to EAT rather than WAT (gambiense) trypanosomiasis, a more slowly progressive, chronic disease.
Measuring the intrathecal IgM concentration may be more appropriate for determining the stage of disease for WAT (Lejon et al., 2003xLejon et al., 2003Lejon, V., Reiber, H., Legros, D., Djé, N., Magnus, E., Wouters, I. et al. Intrathecal immune response pattern for improved diagnosis of central nervous system involvement in trypanosomiasis. J Infect Dis. 2003;
Google ScholarSee all ReferencesLejon et al., 2003). However, for EAT, IgM and various chemokines and other molecular markers of inflammation, alone or in combination, have not been able to categorize patients as having stage 1 or stage 2 disease with the required degree of accuracy (MacLean et al., 2012xMacLean et al., 2012MacLean, L., Reiber, H., Kennedy, P.G., and Sternberg, J.M. Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response. PLoS Negl Trop Dis. 2012;
Google ScholarSee all References, Tiberti et al., 2013xTiberti et al., 2013Tiberti, N., Matovu, E., Hainard, A., Enyaru, J.C., Lejon, V., Robin, X. et al. New biomarkers for stage determination in Trypanosoma brucei rhodesiense sleeping sickness patients. Clin Transl Med. 2013;
Google ScholarSee all References).
None of the cases included in this series seen since 2005 required melarsoprol (Table 1Table 1), despite some having abnormal CSF laboratory findings in the absence of trypanosomes (Table 3Table 3, cases 9, 11, 12). On follow-up testing of one patient (case 9) by a district-level laboratory, there was an apparent false-positive report of trypanosomes in the CSF; on clinical grounds, melarsoprol was not given, and the patient remained well. Adverse drug reactions associated with the administration of suramin, while well described in reference material, are uncommon in practice. They can be avoided by carefully following the recommendations for an initial test dose, carefully evaluating any rashes for alternative causes before attributing them to suramin (for example, an antibiotic-associated rash in case 4), and modifying the suramin dosage in patients with any evidence of trypanosomiasis-associated renal pathology or peripheral neuropathy.
Of the 21 patient cases, one died due to myocarditis, a known complication of stage one EAT (case 3), and one died of melarsoprol encephalopathy following treatment for presumed relapsed CNS disease (case 2). The other patient treated with melarsoprol (case 1) relapsed within 8 months in his home country and developed severe encephalopathy following re-treatment, but survived (Checkley et al., 2007xCheckley et al., 2007Checkley, A.M., Pepin, J., Gibson, W.C., Taylor, M.N., Jäger, H.R., and Mabey, D.C. Human African trypanosomiasis: diagnosis, relapse and survival after severe melarsoprol-induced encephalopathy. Trans R Soc Trop Med Hyg. 2007;
Google ScholarSee all ReferencesCheckley et al., 2007).