Annals of Tropical Medicine & Parasitology, Vol. 94, No. 8, 831-835 (2000)

Clinical and biological evolution of human trypanosomiasis in Côte d’Ivoire

Despite more than 60 years of control activi- ties, human African trypanosomiasis (HAT) remains an important health problem in sub- Saharan Africa. In 1998, for example, the World’ Health Organization estimated that 60 million were at risk of acquiring the disease and that as many as 500000 people were infected with Trypanosoma brucei sspp., the causative agents (WHO, 1998). ‘Two stages of the disease are classically observed: a haemato-lymphatic stage, in which there are no specific clinical signs Uannin et al., 1993; Dumas and Bouteille, 1996), leading to a meningo-encephalitic stage, usually character- ized by neurological disorders. However, hu- man infection with T. b. gambiense-the cause of the usually chronic form of HAT (often known as Gambian sleeping sickness) found in West and Central Africa-may be asymp- tomatic (Gallais et al., 1953; Lapeyssonnie, 1960; Wery and Burke, 1972; Ginoux and Frézil, 1981; Woodruff et al., 1982) or even cause acute disease, as suspected in Côte d’Ivoire (Truc et al., 1997). This diversity in clinical pattern may reflect variation in the parasite, in individual susceptibility to infec- tion, or both. However, the relationship be- tween the genetic diversity of Trj,panosoma brucei sspp. and the clinical evolution of HAT is still a matter of controversy, and marked variation in the susceptibility of humans to infection has never been demonstrated.

In Côte d’Ivoire, 63 people living in the Sinfra area (30 local-born and 33 migrants from Mali, Burkina Faso or northern Côte d’Ivoire) refused treatment for 1-5 years after they had first been found infected with try- panosomes in 1995-1996. Whenever possible and appropriate (see below), each was clini- cally re-examined and re-checked for infection with T. b. gambiense at regular intervals during this period (June 1997, January 1998 and March 1999). Plasma samples were checked

with the card agglutination test for trypanoso- miasis (CATT; Magnus et al., 1978), whole blood was investigated using the miniature anion-exchange centrifugation technique (mAEC?’; Lumsden et al., 1977), and lymph- juice samples (from those with. swollen lymph nodes) were checked under the microscope, for trypanosomes. Although the main aim of these investigations was to persuade those in- fected to accept appropriate treatment, the results obtained are of considerable interest and are therefore reported here.

By the time of the first follow-up, in June 1997. two of the subjects had died (of un- known causes) and 11 had left the Sinfra area, leaving 53 available for re-examination. By the time of the last follow-up, in March 1999, 29 of these 53 had accepted treatment and two more subjects had died, both with severe neuro-psychiatric illness probably attributable to HAT. Only 19 of the original subjects were therefore left untreated and available for the final follow-up. Two of these refused to permit blood samples to be taken from them in March 1999 (although clinical exam- ination of these two at each of the three follow-ups failed to reveal any signs of H A T ) and blood samples were not taken from an- other two subjects at this last follow-up be- cause they had been found to be’ CATT-negative at the first follow-up, in 1997. T h e serological, parasitological and clinical data discussed below are confined to the 15 subjects, here numbered 1-15 for con- venience, who were still untreated at the last follow-up and from whom blood samples were taken at that time (see Table).

Numbers 1-8 were all parasitqlogically negative at the 3-year follow-up, although either CATT-positive in 1999 (numbers 3-8), or CATT-positive in 1997 and 1998 and CATT-negative in 1999 (numbers 1 and 2). Numbers 1-6 had never been found to have

ISSN 0003-4983 (print) ISSN 1364-8594 (online)/00/080831-05 O 2000 1,iverpool School of Tropical Medicine DOI: 1080/00034Y80020028004

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832 JAMONNEAU E T AL.

TABLE Serological, parasitological and clìnical evolution of 1.5 untreaied siibjec[s between parasitologicallJl conjrmed

diagnosis in 1995-1996 and ¡he end of the fillom-up in March 1999

Follolv-up ~~ ~

1995-1 996 June 1997 Janua~y 1998 March 1999

Subject no. .Ttyps C A T T T g y s Signs C A 7 7 Tryps Signs C A T T T y p s Signs

- ND - - ND - + + +

- NA NA NA +

- - - - + + + + +

1 + + +’ 2 + . 3 + - + ” - 4 % + + 5 + + 6 + + 7 + NA NA NA NA NA NA + - s 8 + NA NA NA NA NA NA + - s 9 + + + + + - + + -

+ ’ + - 10 + NA NA NA + + + + + - NA NA NA + + - + + + - NA NA NA + + - 11 12 13 ” ’ + + S + i- -!- + t - s 14 + NA NA NA NA NA NA + + ss 15 + + + + +

- - - - - - - - -

- - - - - - - - - - - -

- - -

- -

- - - - - -

I Tryps, Presence ( -1- ) or absence ( -) of trypanosomes in samples processed by the miniature anion-exchange centrifugation technique; CAT”, positive or negative result after plasma investigated in a card agglutination test for trypanosomiasis; Signs, clinical signs consistent with the first stage (S) of human African trypanosomiasis (fever, headache, asthenia, cutaneous manifestation andlor presence of swollen lymph nodes, but without ncuro-psychiatric disorders) or with the second-stage (SS) of the disease (presence of neuro-psychiatric symptoms such as sleep disturbance, impaired consciousness, unusual behaviour or characzer, impotence, or motor disorders); NI>, not detcrmincd; NA, subject not available for follow-up.

. -

” any signs indicative of HAT during the fol- low-up period, although number 5 had had several clinical signs characteristic of the se-

ever seen with a neuro-psychiatric disorder (and then only at the final follow-up).

The final subject to be considered, number . .’ cond-stage of the-disease (i.e. sleepiness, sex-

ual impotence and behavioural disorders) when first examined in 1995. Numbers 7 and

1 8, who were only available for the March 1999 . . follow-up, where then found to have some of

. :- ’: the clinical manifestations of. HAT. {When ’ . . ’ first examined, in 1996, number 7 had im- . paired consciousness, behavioural disorders

, *

: *’ . and trypanosomes in his cerebro-spinal fluid

r infection, both parasitologically CATT, in March 1999 and when- d during the“ follow-up period,

. ,. ’ ’.,.., . ~ . . . , .

, , . i

. . . , . .. , . . . . ... . . . .

. . .

15, was CATTipositive and parasitologically positive in June 1997 and January 1998 but negative, both by the CATT and the 1 mAECT, at the last follow-up in March 1999. During the follow-up period of the present study, this subject was also examined by staff from the Daloa-based Projet de Recherche Contre la Trypanosomiase (PRCT), in November 1998 and January 1999. On both of these occasions, subject 15 was found negative by the CATT and the mAECT and no try- panosomes could be found in CSF samples. Thus this subject was apparently CATT- negative from November 1998 to the end of the present study.

n

b HUMAN ‘I’KYPANOSOMIASIS IN CÔI’E D’IVOIRT: 833

That 63 trypanosome-infected subjects re- fused treatment for months or even years is disconcerting. Such subjects may simply have wondered why they needed treatment when they felt well (the first stage of HAT being largely asymptomatic), being unaware of how their infection might develop into lethal dis- ease if left untreated. Fortunately, follow-up visits convinced 29 of these subjects to accept treatment, although sometimes only after neurological disorders had developed (data not shown).

The seroconversion, from CA1’T-positivity to CATT-negativity, seen among somc of the subjects who remained asymptomatic throughout the follow-up period (e.g. num-

, bers 1, 2 and 15), is unusual. Subjects 1 and 2, who were never found trypanosome-posi- tive after first being found infected in 1995- 1996, may have had infections with T. congolense (Truc et al., 1998) or T. b. brucei rather than T. b. gambiense. Although T. con- golense and T. b. brircei arc human-serum sen- sitive and probably quickly eliminated, transient infections with these parasites may induce a non-specific immune response and lead to false-positive CAT?’ results because of cross-reactivity (Noireau et al., 1986). I-low- ever, the slow seroconversion observed in sub- jects 1 and 2 is inconsistent with a transient infection with a non-human parasite, since such infections are unlikely to maintain CA‘YJ’ positivity for 2 or 3 years.

Trypanosomes isolated from subject 15, who had become CA1’T-negative by Novem-, ber 1998, were confirmed to be of T. h. gambiense group 1 (Gibson, 1986) by multi- locus enzyme electrophoresis (MIXE; Jamonneau e l al., 2000). Thus, subjects 1, 2, and 15 were probably infected with T. b. gambiense when first examined in 1995-1996, and probably became CA1’T-negative by March 1999 as the result of clearance of their infections, even though they had not been treated with ‘conventional’ medicine. These three cases were therefore probably examples of self-cure, although some of the present sub- jects (3, 5’ and 15) were followed-up and probably partially treated by a ‘healer’. ‘The efficacy of traditional medicines used to treat

1

HAT remains unclear and must be investigated. The present data confirm that HAI‘ is

diverse in its clinical evolution, with infections that remain asymptomatic (Gallais et al., 1953; Ginoux and Frk i l , 1981) and some apparent cases of self-cure as well as those that lead into the second-stage of the disease, with chronic or acute neurological disorders. This variation may be associated with genetic variability in the parasites, as observed in Uganda (Smith and Bailey, 1997). However, the genetic varia- bility of trypanosome stocks from Côte d’Ivoire, mostly collected in the Sinfra area, has always appeared to be very low, whether investigated using the repetitive sequences of microsatellite DNA and PCR (Biteau et al., 2000), RAPD or MLEE Uamonneau et al., 2000). The results of MLEE (Jamonneau et al., 2000) have, in fact, indicated that the parasites infecting subjects 9-15 in the present study belonged to the same zymodeme, and no relationship between zymodeme and patho- genicity in humans has ever been noticed in studies in Côte d’Ivoire.

Is variation in human response to the infec- tion, rather than variation in the parasite, responsible for the diversity in clinical evol- ution? Ginoux and F’rézil (1981) suspected that asymptomatic infection, with low para- sitaemia, no swollen lymph nodes and no neurological sign, was the result of human trypanotolerance. Such a phenomenon may explain why subjects 3-8 in the present study remained CA‘YI’-positive but apparently apar- asitaemic (Kabiri et al., 1999). Although the trypanotolerant individual may remain asymp- tomatic for several years, the equilibrium may bc broken, leading to the sudden appearance of nervous disorders, as observed in other trypanotolerant animals (Murray et al., 1990; Authié, 1994). Variation in individual suscep- tibility to infection has been already demon- strated for both viral (Michael er al., 1997) and bacterial infections (Altare et al., 1998) and the results of numerous studies indicate that host genetics play a role in susceptibility to infection with some parasites (Marquet et al., 1996; Garcia el al., 1999). In mice, genes on chromosomes 5, 11 and 17 of the host are involved in resistance to T. congolense (Kemp

I

. .-

. .......... 1) . . . .I. #

et al., 1997), and indirect data indicate a similar link in human infection with T. 6. rlzodesiense (Okia et al., 1994). In Central Africa, the trypanolytic activity of sera from Bantus is markedly different to that of sera from Pygmies (Authié et al., 1991). Further investigation is needed to see if ethnicity (and

' therefore genetics) affects susceptibility to HAT, in the same way that it affects suscepti- bility to leishmaniasis (Alcais el al., 1997).

.

ACKNO\I'I~I:I)GI:.MI:N'I'S. We would like to ex- press our sincere thanks to the staff of the Institut Pierre Richet/OCCGE at Bouaké (CGte d'lvoire) for their excellent technical help. This work was supported by Fonds d'Aide à la Coopération, Ministère français des Affaires Etrangères, Direction du Dével- oppement et de la Çoopération technique, and the Institut de Recherche pour le DCveloppe- ment.

lnstitut Pierre Kichet,' B.P. 1500; Uouak6 01, Côte d'lvoire, and Département Sociétés e! Santé, Institut de Kecherche pour le IXveloppem&nt (IRD-ex ORSI'OM), 91 1 Avenue Agropolis, 34032 Montpellier, France

Développement (IRD-ex OKSI'OM), 91 1 Avenue Agropolis, 34032 France

Y. "GUIISSAN L. "DKI R. SANON Unité de Recherche et de Lutte contre la THA, Institut I1ierre Richet, B.P. 1500, 13ouaké 01, CBte d'Ivoire

c. ,AVI:ISSIfiKI: 13épartement lh Sociétés et Santé, Institut de Recherche pour le Dtveloppement (IRD-ex ORSTOM), 91 1 Avenue Agropolis, 34032 Montpellier, France, and Laboratoire de Recherche sur les Trypanosomoses, OCEAC, B.P. 288, Yaoundé, Cameroon .

P TRUC*

Ir i épartenient Sociétés et Santé, Institut de Recherche pour le Développement (Ilw-ex ORSI'OA/I), 91 1 Avenue Agropolis, 34032 Montpellier, France, and Laboratoire dc Recherches et de Coordination sur les Trypanosomoses

Received 28 3 'dy 2000, Revised 12 September 2000, Accepted 14 Sepiember 2000

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