We presented the first case of sleeping sickness imported to Poland, and the first case of documented Trypanosoma brucei infection in a tourist from Central-Eastern Europe. Moreover, this was the first recorded case in the past 25 years of acute-stage East African trypanosomiasis occurring in a European traveller infected in Uganda (Eastern Africa).
Although East African trypanosomiasis is hyperendemic in the south-eastern part of Uganda, it has spread to the western and central parts of the country during the last decade, and this is partially due to the movement of cattle and their local trading to these regions from the original infection belt. In fact, HAT has become a re-emerging parasitic infection of public health concern in Uganda, where the geographical distribution of tsetse fly-affected areas has extended to previously uninfected provinces [5–8, 11]. According to the National Sleeping Sickness Control Program in Uganda, more than 2,500 presumed T. b. rhodesiense cases have been reported since 2000, and mortality rates are higher in recently affected districts. The disease has a tendency to a seasonal transmission with the highest risk from January to March, as spreading of infection is mostly related to livestock migration and cattle trading .
Among all HAT cases imported to Europe since 2005, most of them were expatriates or immigrants returning from sub-Saharan Africa; but during the last years an increasing number of sleeping sickness has been reported in tourists [1, 13–16]. Over the last decade, non-endemic human infections with T. brucei in European travellers have been reported mainly from Tanzania, Gabon, Zambia, Angola, Guinea, Malawi and Central African Republic. So far, imported HAT cases have been registered in France, Italy, Spain, the United Kingdom, Belgium, Germany, the Netherlands, Switzerland and Scandinavia [1, 2, 17–24].
The presented patient did not comply with any tropical hygiene measures, and wore inappropriate clothing in areas at risk. European tourists travelling to destinations with a significant risk of HAT, such as national parks, nature reserves and safari camps, should be instructed on preventive measures against tsetse bites, particularly wearing long sleeve shirts and trousers made of a thick cotton material, without bright or contrasting colours, impregnated with permethrin, as well as regular application of insect repellents. If skin symptoms occur, consultation with an experienced travel medicine clinician should be considered as a matter of urgency, in order to reduce the high fatality rate if generalised signs of HAT develop. As in the case of our patient, an inoculation chancre is typically present in nearly all reported patients with imported HAT [1, 18, 20, 22–24], and it is a clinical sign of utmost importance in guiding the differential diagnosis . It may be mistaken for a rickettsial chancre by less experienced health practitioners or simply overlooked with potentially disastrous consequences . According to Odiit and colleagues, most HAT cases that originated from epidemic areas in Uganda were not diagnosed by the national health care system, including fatal cases, despite their contact with medical facilities .
Early diagnosis and prompt administration of effective anti-parasitic treatment are the key prognostic factors in a patient’s clinical prognosis and increase the probability of survival. In HAT caused by T. b. rhodesiense, the disease has a tendency of rapid progression to the stage of central nervous system involvement between 3 weeks to 2 months after a primary infection. Most HAT deaths are reported within the first 6 months of clinical manifestations [27–29].
The role of the geographical location, parasite genotype and specific host inflammatory cytokine response in the clinical expression of the disease in humans has been studied by many authors. Currently, an analysis of some genetic markers of T. b. rhodesiense virulence seems to be the best option for a predictive evaluation of HAT cases, and a practical determination of clinical course severity. MacLean et al. reported that infections with the Tororo genotype were characterised by an increased probability of disease progression and a rapid development of the meningoencephalitic stage, and higher plasma interferon gamma levels, while the Soroti genotype was well correlated with a milder clinical course of HAT cases . Similarly, severe clinical status of HAT patients and its rapid progression to meningoencephalitis in T. b. rhodesiense infections from Uganda was related to elevated concentrations of tumour necrosis factor alpha (TNF-alpha) in serum samples. On the contrary, more benign infections with T. b. rhodesiense in Malawi were associated with high levels of transforming growth factor beta but not TNF-alpha activation .
In the reported case, circulating trypomastigotes were easily identified in the peripheral blood samples collected on admission at the emergency room, and stained by Giemsa. The short incubation period of the infection and the severe clinical status of the patient, accompanied by multi-organ injury, suggested an acute Rhodesian form of HAT caused by a highly pathogenic strain. Molecular differentiation of T. brucei complex by finding the characteristic SRA gene and S-locus glycoprotein gene polymorphism marker of T. b. rhodesiense subspecies, in whole blood collected before treatment, using a PCR technique, considerably improved the diagnostic accuracy and finally confirmed the clinical diagnosis (Table 1).
The SRA gene, first isolated from a Ugandan strain of T. b. rhodesiense, has been shown to be a marker of the parasite invasiveness for humans. This gene has also been identified in several other isolates of T. b. rhodesiense from Ethiopia, Kenya, Tanzania, Zambia and Botswana, but not in the other human pathogenic trypanosomes in Africa, including T. b. gambiense[13, 30]. Further analysis showed a significant SRA gene polymorphism and differences in immune response profiles in host populations from variable geographical areas . Strain typing using microsatellite markers has proven the molecular heterogeneity between different T. b. rhodesiense isolates, which can be related to considerable differences in the degree of infectivity to human beings according to genetic variants .
Serological diagnosis, particularly the CATT widely used in the field by medical officers, is more helpful in T. b. gambiense infections, when trypomastigotes may be difficult to be found in the peripheral blood or lymph. Home-made IFAT or ELISA performed in scientific laboratories is very useful for the differential diagnosis between both subspecies. In the case described above, we detected a seroconversion of immunoglobulin (Ig) M and IgG specific antibodies in the peripheral blood by ELISA on the 7th day of hospitalisation or 15th day of clinical symptoms. Total IgM reached the highest level on the 7th day of treatment and persisted longer than Trypanosoma-specific immunoglobulins. Serological tests for T. b. gambiense subspecies (CATT, IFAT, ELISA) were all negative, confirming the final diagnosis (Table 1).
Pentamidine is recommended to be the standard therapy for acute West African trypanosomiasis. Suramin is generally considered as the drug of choice for an early stage of Rhodesian sleeping sickness; melarsoprol alone or in a combination with nifurtimox is proposed for a late stage of the illness [3, 13, 31, 32]. A combined therapy with suramin and eflornithine seems to be very promising [32, 33]. In case of unavailability of suramin, treatment with pentamidine plays a crucial role in the prevention of severe complications of second-stage HAT, characterised by poor clinical prognosis . In a large study of 56 travellers from non-endemic countries infected with T. b. rhodesiense, 7% were treated with pentamidine alone . In some other patients with early stage of Rhodesian sleeping sickness, anti-protozoan therapy with pentamidine has been initiated and then switched to suramin upon availability . Therefore, pentamidine is accepted to be an alternative drug for the management of an early phase of T. b. rhodesiense infection .
Among all imported cases of East African trypanosomiasis reported in the literature, this was also the first documented patient successfully treated with pentamidine instead of suramin, despite the critically high parasitaemia, which is extremely rarely observed. After the administration of suramin, the blood stage trypomastigotes disappeared within 3 days in all recently imported cases [13, 16]. This was finally observed in this patient treated with pentamidine alone. Following the elimination of parasitaemia, clinical recovery occurred fairly rapidly. Clinical symptoms and laboratory parameters of multi-organ injury resolved within 10 days, without late complications. There have been no signs of disease persistence or relapse during the 3 years of clinical follow-up.
Patients should usually be followed-up for 3 months (acute haematogenous stage) or for up to 2 years (meningoencephalitic stage), to confirm complete eradication. There is a risk of the chronic suppression of the disease in improperly treated patients . In this case, anti - T. b. rhodesiense IgM-IgG antibodies were observed in serum samples for 4 weeks and were later not detectable. Total IgM lasted longer, but after significantly rising 1 week after admission to hospital, it tended to diminish during the follow-up period (Table 1). During serological monitoring, serum IgM levels may actually increase before they finally decrease, and should not be regarded as a sign of treatment failure. Serum antibodies may appear well after the commencement of treatment, and diminish over time with the elimination of parasites. A 2-fold reduction in serum antibody titre may be interpreted as a sign of at least temporary parasite reduction, but it cannot be used to ascertain definitive cure . Further analysis of some genetic markers of sensitivity and/or resistance to pentamidine in T. b. rhodesiense strains from Uganda has been promising.