Accepted Manuscript

Title: Clinical presentation and treatment outcome of sleepingsickness in Sudanese pre-school children

Authors: Gilles Eperon, Caecilia Schmid, Louis Loutan,Francois Chappuis

PII: S0001-706X(06)00243-9DOI: doi:10.1016/j.actatropica.2006.12.002Reference: ACTROP 1907

To appear in: Acta Tropica

Received date: 16-6-2006Revised date: 30-10-2006Accepted date: 7-12-2006

Please cite this article as: Eperon, G., Schmid, C., Loutan, L., Chappuis, F., Clinicalpresentation and treatment outcome of sleeping sickness in Sudanese pre-schoolchildren, Acta Tropica (2006), doi:10.1016/j.actatropica.2006.12.002

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Clinical presentation and treatment outcome of sleeping sickness in

Sudanese pre-school children

Gilles Eperona,b, Caecilia Schmidc, Louis Loutanb, François Chappuisa,b

a Médecins sans Frontières, rue de Lausanne 78, 1202 Geneva, Switzerland

b Travel and Migration Medicine Unit, Geneva University Hospitals, rue Micheli-du-Crest 24,

1211 Geneva 14, Switzerland.

c Swiss Tropical Institute, Socinstrasse 57, P.O. Box, 4002 Basel, Switzerland

Corresponding author : Dr François Chappuis, Travel and Migration Medicine Unit, Geneva

University Hospitals, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland

Tel: 41-22-3729620; Fax: 41-22-3729626; e-mail : francois.chappuis@hcuge.ch

* 3. Manuscript revised

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Abstract :

Background: existing data on Human African trypanosomiasis (HAT) due to Trypanosoma

brucei gambiense among children are limited. Here, we described the demographic, clinical,

diagnostic, treatment and outcome characteristics of HAT in pre-school children from Kajo-

Keji County, South-Sudan in comparison with older patients.

Methods: we did a retrospective analysis of HAT patients treated at the Kiri Sleeping

Sickness Treatment Centre (SSTC), Kajo-Keji County, from June 2000 to December 2002.

Results: of 1958 HAT patients, 119 (6.1%) were pre-school children (< 6 years) including 56

(47%) in first-stage illness and 63 (53%) in second-stage. The proportion of children in

second-stage HAT was significantly higher in very young children (< 2 years). Walking and

speech disturbances were more frequent in second-stage HAT but other neurological

symptoms and signs were not associated with disease stage. Pentamidine treatment for first-

stage illness was very safe and effective among pre-school children. In contrast, 4.9% of pre-

school children in second-stage illness died during melarsoprol treatment and 46% had > 1

severe adverse event(s). Macular rash, jaundice and skin necrosis on injection site were

significantly more frequent in this age group (p < 0.05). Melarsoprol-induced encephalopatic

syndrome was less frequent but more severe than in older age groups.

Conclusion: the clinical features of T. b. gambiense HAT among pre-school children are

insufficiently stage-specific. Therefore, laboratory-based staging is mandatory to prevent

unnecessary harm to HAT patients caused by the high toxicity of melarsoprol.

Key words : African trypanosomiasis, Sleeping sickness, children, pentamidine,

melarsoprol, adverse events

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1. Introduction :

Human African Trypanosomiasis (HAT) due to Trypanosoma brucei gambiense re-

emerged as a major public health problem during the last 20 years in several central African

countries such as the Congos, Angola, Sudan and Uganda (Moore and Richer, 2001; Pepin

and Meda, 2001). Fortunately, the epidemiological trend seems to be reversing in the most

affected countries thanks to increased control activities (Abel et al., 2004; Lutumba et al.,

2005; WHO, 2006).

There is little data published on HAT among children in pre-school age (under 6 year old)

and the incidence in young children seems lower than in adults (Pepin and Meda, 2001; Snow

et al., 1991; Triolo et al., 1985). The clinical presentation in pre-school children ranges from

the absence of symptom to severe neuro-psychiatric disorders (Cramet, 1982; Debroise et al.,

1968; Kazumba et al., 1993; Koko et al., 1997; Le Bras et al., 1977; Ngandu-Kabeya, 1976;

Triolo et al., 1985). A short first- (haemo-lymphatic) stage and an overlap of clinical signs

between first- and second- (meningo-encephalitic) stages, the latter being also observed in

adults, have been described (Le Bras et al., 1977; Triolo et al., 1985).

Intramuscular pentamidine has been widely used to treat first-stage HAT and is described

as safe and efficient in all age groups. However, most studies were conducted in

immunosuppressed children infected by Pneumocytis carinii (Hughes et al., 1978; Hughes et

al., 1973; Walzer et al., 1974).

Melarsoprol and eflornithine are the only therapeutic options for second-stage T. b.

gambiense HAT. Melarsoprol is an arsenic-based derivative and is associated with

encephalopatic syndromes (ES) in 5 to 10% of treated patients with a case-fatality rate of

around 50% (Pepin and Milord, 1994). Eflornithine is safer than melarsoprol (Chappuis et al.,

2005; Balasegaram et al., 2006) but its high cost and complicated administration limit its wide

use in HAT treatment.

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As few studies have been conducted in pediatric patients with HAT, we performed a

retrospective analysis of clinical data routinely collected during a sleeping sickness control

programme run by Médecins sans Frontières (MSF) in Kajo-Keji County, southern Sudan.

Here, we report a full description of the demographic, clinical, diagnostic and treatment

outcome characteristics of T. b. gambiense HAT in pre-school children compared to older

patients.

2. Patients and Methods

Patient population: Kajo-Keji County is in the Sudanese Province of Western Equatoria,

bordered by Uganda, and is inhabited by around 95’000 people (census 2001). A total of 1958

patients with HAT, 850 (43%) in first-stage and 1108 (57%) in second-stage, were treated

between June 2000 and December 2002 in the MSF Kiri sleeping sickness treatment centre

(SSTC). Nearly 80% of these patients were detected by passive screening.

Screening, diagnosis and staging: The diagnostic algorithm used was shown elsewhere

(Chappuis et al., 2002). Briefly, all individuals were screened by the Card Agglutination

Trypanosoma Test (CATT) on whole blood and on diluted serum (CATT 1:4) (Magnus et al.,

1978), and by a clinical search for cervical lymph nodes (CLN). In CATT 1:4 positives,

trypanosomes were looked for in CLN by direct microscopic examination of puncture

material, in the blood by the micro-hematocrit concentration test (mHCT) or by the

Quantitative Buffy Coat (QBC), and in the cerebrospinal fluid (CSF) after double

centrifugation. A white blood cell (WBC) count in the CSF was performed in all these

individuals.

First-stage HAT was defined by the presence of trypanosomes in CLN or blood with CSF

examination showing no trypanosomes and < 5 WBC/mm3. Second-stage HAT was defined

either by (1) the presence of trypanosomes in the CSF or, (2) the presence of trypanosomes in

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CLN or blood with > 5 WBC/mm3 in the CSF or, (3) a CATT 1:4 positive and > 20

WBC/mm3 in the CSF.

Clinical assessment: All patients admitted in Kiri SSTC had a full history taken and

clinical examination performed on admission by a physician or an experienced clinical

officer. Clinical history and admission examination data were gathered in different case-report

forms distinct for first- and second-stage patients.

Treatment: First-stage patients were treated with intramuscular pentamidine isethionate, 4

mg/kg daily for 7 days. No other drugs were given unless required by clinical or laboratory

findings. Sweet tea or food was given at the time of injection to avoid hypoglycaemia and bed

rest was recommended for one hour after injection to avoid symptomatic hypotension. In case

of alteration of behaviour or state of consciousness, hypoglycaemia was considered and

treated promptly. Second-stage patients were treated with melarsoprol 2.2 mg/kg daily by

slow intravenous injection for 10 days (Schmid et al., 2005). All patients received oral

prednisolone 1mg/kg during treatment. A therapeutic dose of pyrimethamine-sulfadoxine

(chloroquine in infants < 6 months) was given at days 0 and 7. Mebendazole (for patients

older than 2 years), multivitamins, folic acid and iron supplementation were also routinely

given. Severely malnourished patients were fed orally or by naso-gastric tube for 3 to 5 days

before melarsoprol was started. Relapses were treated with eflornithine 400 mg/kg/day (600

mg/kg/day in patients < 12 years) in 4 divided infusions for 7 days.

Assessment of adverse events: Adverse events were recorded daily and graded as 0 (none),

1 (mild to moderate) or 2 (severe). Encephalopatic syndromes (ES) were graded as 1

(psychotic reaction) or 2 (repeated or prolonged seizures or rapid deterioration of the level of

consciousness). “Melarsoprol reaction”, considered as a warning sign for ES, was diagnosed

if more than one of the following symptoms or signs were present: headaches unresponsive to

paracetamol, sudden onset of fever not caused by malaria, scleral injection, major dizziness or

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new onset of tremor. Both, ES and melarsoprol reactions were treated with high dose

intravenous dexamethasone until 24 hours after clinical improvement. Other drugs such as

chlorpromazine or diazepam were used as required and melarsoprol was temporarily

suspended until symptoms resolved. In case of recurrent melarsoprol reactions/ES, since May

2001 eflornithine was used to complete treatment. Melarsoprol treatment was considered

completed if at least 8 doses were administered.

Follow-up: All patients were asked to come for follow-up visits 6, 12 and 24 months after

hospital discharge. At each visit, a search of trypanosomes was performed in blood and CSF,

and the WBC count in the CSF was determined. Relapse was diagnosed when (1)

trypanosomes were visualised in blood or CSF or (2) the WBC count in the CSF significantly

increased compared to the previous control or (3) the WBC count in the CSF showed little

variation compared to previous control and the patient had symptoms and signs consistent

with HAT. Definite cure was defined as the absence of relapse at the last follow-up visit, 24

(range: 18-30) months after hospital discharge. If the last follow-up visit was not

accomplished, probable cure was defined as the absence of sign of relapse at the first and/or

second visit (3 to 17 months after discharge). Patients who did not attend at least one follow-

up visit were defined as lost to follow-up. Treatment failure was defined as relapse or death

occurring during treatment or follow-up (unless an obvious external cause of death was

reported).

Data collection and analysis: Demographic, laboratory, treatment and clinical outcome

data were entered monthly in YoTryp, a Microsoft Access-based software designed by MSF.

As symptoms and signs were not computerized in YoTryp, these data were recorded

separately. Data were analysed using SPSS 11.0 for Windows (SPSS Inc., Chicago, IL, USA).

A comparison by age groups (< 6, 6-15 and > 15 years) of the main variables was performed.

Numerical variables were summarised by mean and standard deviation (S.D.) if normally

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distributed, otherwise by medians and quartiles. Categorical variables were compared using

cross-tabulations and chi-square tests or Fisher’s exact test whereas numerical variables

(means) were compared with Student’s t-test, at a critical α-level of 0.05. All P-values were

two-sided.

3. Results :

Out of the 1958 HAT patients treated during the period covered by our study, 119 (6.1%)

and 475 (24.2%) were aged under 6 and 6 - 15 years, respectively. Second-stage illness was

diagnosed by the finding of trypanosomes in CLN or blood with > 5 WBC/mm3 in the CSF in

most patients (92.7%) whereas 7% had a CATT 1:4 positive with > 20 WBC/mm3 in the CSF

and 0.3% had trypanosomes with < 5 WBC/mm3 in the CSF.

Comparison of first- and second-stage HAT among pre-school children

First- and second-stage illnesses were diagnosed in 56 (47%) and 63 (53%) pre-school

children, respectively. The proportion of second-stage varied significantly with age (p =

0.027), being higher in very young (< 2 years) pre-school children (figure 1). Pre-school

children in second-stage were significantly likelier to present with fever, malnutrition and

walking disturbances than in first-stage (p < 0.05). Other neurological symptoms and signs

were found with similar frequencies in first- and second-stage. Tremor and abnormal

movements were very rare clinical findings (table 1).

Comparison of baseline medical data between pre-school children and older patients

The prevalence of CLN was significantly lower in children below 2 years compared to

older age groups in both first-stage (13% versus 40%; p = 0.05) and second-stage (15% versus

54%; p < 0.001). Trypanosomes were found with lower frequency in CLN and with higher

frequency in blood among pre-school children with second-stage illness. A lower proportion

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of pre-school children had < 20 white blood cells/mm3 in the CSF compared to other age

groups (table 2).

Treatment, adverse events and clinical outcome

Treatment outcome and adverse events were assessed in 54 pre-school children and 766

older patients with first-stage HAT treated with pentamidine (table 3). Significantly fewer

children had hypoglycemia than adults (p = 0.04). No death occurred during treatment among

pre-school children. One death of unknown cause, but no relapse, occurred during follow-up.

Treatment outcome and adverse events were assessed in 1029 second-stage HAT patients

treated with melarsoprol, including 61 pre-school children (table 4). Melarsoprol was poorly

tolerated in all age groups. Fever and melarsoprol reaction were more frequent in children (p

< 0.05), whereas symptoms and signs consistent with polyneuropathy were less frequently

reported. Headaches and tremor were significantly less frequent in pre-school children and no

case of hypertension occurred in this age group. Macular rash, skin necrosis on injection site

and jaundice were significantly more often found in pre-school children. Very low age (under

2 years) appeared to be at special risk as 8.7% developed jaundice and 32% a macular rash in

this group, these proportions being significantly higher than in older (2-5 year old) pre-school

children (p < 0.001).

We found a trend towards a lower risk of ES in pre-school children (3%) than in older

children (10%) and adults (13%), but a significantly higher ES-caused case-fatality (100%

versus 38% and 24%, respectively). With an in-hospital death rate of 4.9% and an overall

treatment failure rate of 8.2%, pre-school children had a comparable immediate and final

outcome as found in older patients.

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4. Discussion:

We report here one of the largest study on T. b. gambiense HAT in young children and

include a first description of clinical characteristics and treatment outcomes in this age group

in Sudan.

Pre-school children in second-stage HAT were significantly younger than those in first-

stage, and a higher proportion of second-stage illness was found in very young children (< 2

years) than in older children. This predominance of second-stage illness in young children

was previously reported (Cramet, 1982; Debroise et al., 1968; Ngandu-Kabeya, 1976; Triolo

et al., 1985). Late diagnosis is a likely explanation supported by several authors (Kazumba et

al., 1993; Le Bras et al., 1977; Triolo et al., 1985), as the clinical presentation in very young

children can be difficult to differentiate from other febrile illnesses. A more rapid transition

from first- to second-stage illness in very young children (Le Bras et al., 1977; Triolo et al.,

1985), due to the immature blood-brain barrier during the first year of life (Wenzel and

Felgenhauer, 1976), could also be an explanation. Moreover, as very young children may

have >5 WBC/mm3 in the CSF without evidence of neurological disorder, some degree of

over-classification into second-stage illness might have occurred (Ammon and Richterich,

1970; Portnoy and Olson, 1985). As none of the children were diagnosed during their first 5

days of life (De Raadt, 1985), we cannot confirm the presence of congenitally acquired HAT

in our cohort.

Most symptoms and signs were found with similar frequencies in first- and second-stage

pre-school children. Speech and walking disturbances were the only neurological signs

associated with second-stage illness. Other neurological signs such as impairment of

consciousness, abnormal movements, tremor or motor weakness, previously associated with

second-stage HAT (Boa et al., 1988; Cramet, 1982), were rare findings in our study. Sleep

disturbance did not discriminate between stages, as previously found (Cramet, 1982; Ginoux

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et al., 1982; Le Bras et al., 1977). The short duration of first-stage could contribute to this

overlap that appears more obvious in children than in adults (Le Bras et al., 1977). Therefore,

disease staging in particular in pre-school children must rely on careful examination of the

CSF.

Cervical lymph nodes (CLN) were significantly less frequent in very young (< 2 years)

children in both disease stages. A similar conclusion was made among more than 2500

second-stage patients from several African countries (Blum et al., 2006). Lymphadenopathy

in young children has been described as small and could thus be more easily missed during

routine search (Debroise et al., 1968). The low sensitivity of CLN palpation is a definite

argument for using more sensitive screening tools such as the CATT (Magnus et al., 1978).

We found no relapse among 54 pre-school children treated with pentamidine. A higher rate

of relapse was found among children treated with sequential pentamidine and suramine in

DRC, leading the authors to recommend the use of higher doses of pentamidine in children

(Pepin and Khonde, 1996). Our data do not support this recommendation in the South

Sudanese endemic focus.

Pentamidine was found to be safe in pre-school children with no death or severe adverse

events reported. The profile of adverse events was similar to previous reports in children or

adults who received pentamidine for HAT or Pneumocystis carinii pneumonia (Hughes et al.,

1978; Pepin and Milord, 1994; Sands et al., 1985; Walzer et al., 1974). We found a trend

towards a lower incidence of adverse events in children (23%) compared to adults (31%; p =

0.09), due to a significantly lower occurrence of hypoglycaemia. As most hypoglycaemic

episodes were diagnosed clinically, it is likely that some degree of under-detection occurred

in children.

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The 10-day schedule of melarsoprol was shown to be highly effective in Kajo-Keji

County, with low relapse rates in pre-school children (1.6%), older children (3.9%) and adults

(2.3%).

The toxicity of melarsoprol was high as 69% of pre-school children suffered from one or

more adverse events, graded as severe in two-thirds of cases. We found a trend towards a

lower incidence of ES in pre-school children (3.3%) than in older children (10.4%) and adults

(12.9%). A similar trend was observed in DRC and Ivory Coast (Haller et al., 1986; Pepin et

al., 1995), but not in Cameroon (Triolo et al., 1985). The case-fatality rate of ES was found to

be significantly higher in pre-school children than in older age groups, but these finding must

be interpreted with caution as only two children developed ES in our cohort. The increased

incidence of fever among children can be caused by a differential direct effect of melarsoprol

in this age group or by an increased incidence of concomitant infections such as malaria.

Macular rash and jaundice were more frequently observed in the youngest patients. This can

be due to an increased direct toxicity of melarsoprol or an increased occurrence of immuno-

allergic reaction. Skin necrosis due to paravenous injection was more frequent in young

children because of the small vein size and the higher risk of uncontrolled movement during

injection. Under-reporting of symptoms by children is likely to explain the decreased

incidence of headache and polyneuropathy. Interestingly, tremor was an exceptional finding

in young children treated with melarsoprol. This could be explained by a decreased toxicity of

melarsoprol or by milder lesions caused by HAT in some specific areas of the brain. The latter

hypothesis is supported by the rareness of tremor reported on admission in this age group.

The 4.9% in-hospital case-fatality rate among second-stage pre-school children treated

with melarsoprol in Kajo-Keji is comparable with the other age groups included in our cohort

and with previous published data (Pepin and Milord, 1994; Schmid et al., 2005). Eflornithine

was introduced as first-line treatment for second-stage HAT in Kajo-Keji since January 2003

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and has since been shown to be significantly safer than melarsoprol (Chappuis et al., 2005).

Eflornithine should be considered as the preferred treatment for second-stage HAT but its

widespread use remains limited by logistic, cost and human resources constraints. Moreover,

intravenous access in young children for 14 days is an additional challenge. There is an urgent

need for new drugs against second-stage HAT but, at the time of writing, no molecule has

reached pre-clinical stages of development.

In conclusion, pre-school children with HAT present with various and poorly specific

clinical features that could contribute to delayed diagnosis and treatment, leading to more

advanced brain damage. Laboratory staging remains crucial as the clinical presentation does

not reliably discriminate between stages and as the treatment of second-stage is either toxic

(melarsoprol) or complicated to administer (eflornithine).

Acknowledgements

We thank the Sudanese and expatriate medical and laboratory staff of Kiri SSTC for their

dedicated work, as well as Dr M. Aldenkortt for having kindly revised the manuscript.

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Figure 1: proportion of patients with first- and second-stage HAT according to age group in

Kiri SSTC, southern Sudan

0%10%20%30%40%50%60%70%80%90%

100%

0-1 year (n=42) 2-5 years(n=77)

6-15 years(n=475)

> 15 years(n=1364)

Age category

Prop

ortio

ns

First-stage HAT Second-stage HAT

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Table 1: comparison of clinical characteristics in pre-school children with first- and second-

stage HAT in Kiri SSTC, southern Sudan. Data expressed as n (%).

Characteristicsa First-stage HAT

n (%)a

Second-stage HAT

n (%)a

p-valueb

Age : mean (S.D.) 2.93 (1.51) 2.29 (1.49) 0.02

Clinical characteristics

Symptoms

- Weight loss 36 (86) 37 (70) 0.07

- Joint pain 32 (76) 32 (62) 0.13

- Headache 33 (85) 34 (68) 0.07

- Pruritus 29 (67) 31 (59) 0.37

- Sleep disorder 25 (58) 28 (53) 0.60

- Behaviour change 21 (53) 24 (47) 0.61

- Speech disturbancec 0 (0) 9 (41) 0.07

- Consciousness impairmentd 0 (0) 4 (8) 0.58

Signs

- Fever (on day of admission) 4 (9) 21 (40) 0.001

- Cervical lymph nodes 21 (38) 17 (27) 0.22

- Hepatomegaly 15 (37) 19 (37) 1.0

- Splenomegaly 35 (81) 35 (66) 0.06

- Dehydration 0 (0) 3 (6) 0.25

- Malnutrition 5 (12) 17 (32) 0.02

- Edema of the face 3 (7) 2 (4) 0.65

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- Edema of the legs 1 (2) 1 (2) 1.0

- Abnormal movements NR 1 (2) -

- Walking disturbancese 1 (4) 12 (41) 0.001

- Tremor NR 1 (2) -

- Motor weaknessf 0 (0) 4 (8) 1.0

Abbreviations : NR = not recorded, S.D. = standard deviation.

a. Denominator: n = 119 patients (1st stage: 56; 2nd stage: 63) for prevalence of cervical lymph

nodes; n = 89-96 (1st stage: 39-43; 2nd stage: 50-53) for other clinical characteristics unless

indicated

b. P-value measured by Pearson Chi-square or by Fisher’s exact test (if > 1 cell with value <5)

for categorical variables and Student-t test for numerical variable (age)

c. Only assessed in children > 24 months old (n = 48), data from 18 patients missing

d. Data from 35 patients missing

e. Only assessed in children > 18 months old (n = 57); data from 1 patient missing

f. Data from 39 patients missing

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Table 2: Comparison of baseline laboratory characteristics among different age-groups in 1958 patients with first and second-stage HAT in Kiri

SSTC, southern Sudan. Data expressed as n (%).

Characteristics First-stage HAT (total n = 850) Second-stage HAT (total n = 1108)

0 – 5 years

n = 56

6 – 15 years

n = 226

> 15 years

n = 568

P-valuea

0 – 5 years

n = 63

6 – 15 years

n = 249

> 15 years

n = 796

P-valuea

Presence of trypanosomes

- in cervical lymph nodes 19 (34) 76 (34) 154 (28) 0.15 12 (19) 122 (49) 371 (47) < 0.001

- in blood 37 (66) 148 (66) 409 (72) 0.03 37 (59) 74 (30) 293 (37) <0.001

- in cerebro-spinal fluid (CSF) - 26 (41) 96 (39) 338 (43) 0.55

White blood cells in CSF (/mm3)

- < 20

- 21-100

- > 100

12 (19)

33 (52)

18 (29)

76 (31)

95 (38)

78 (31)

221 (28)

264 (33)

311 (39)

0.009

a. P-value measured by Pearson Chi-square

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Table 3 : Adverse events and clinical outcome by age category in 820 patients with first-stage

HAT treated with pentamidine in Kiri SSTC, southern Sudan. Data expressed as n (%)

0 – 5 years old

n = 54

6 – 15 years old

n = 225

> 15 years old

n = 541

P-valuea

Adverse eventsb

All 11 (23) 45 (23) 154 (31) 0.09

Severe 0 (0) 0 (0) 0 (0) -

Type

- Abscess (injection site) 0 (0) 5 (3) 10 (2) 0.53

- Hypoglycemia 8 (17) 37 (19) 134 (27) 0.04

- Pancreatitis 0 (0) 1 (1) 0 (0) 0.25

- Hypotension 0 (0) 0 (0) 3 (1) 0.48

- Vomiting 5 (10) 11 (6) 21 (4) 0.16

Outcome

Issue at discharge 0.77

- discharged alive 54 (100) 225 (100) 540 (99.8)

- in-hospital death 0 (0) 0 (0) 1 (0.2)

Attendance to follow-upc 32 (60) 195 (87) 425 (79) <0.001

Follow-up outcomed 0.002

- Definite or probable cure 32 (60) 184 (82) 404 (75)

- Relapse 0 (0) 11 (5) 21 (4)

- Death 1 (2) 0 (0) 3 (1)

Treatment failuree 1 (2) 11 (5) 25 (5) 0.61

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a. P-value measured by Pearson Chi-square

b. Missing data in 6, 27 and 43 patients in the 0-5, 6-15 and > 15 year old groups, respectively

c. Definition: > 1 control within 24 months after discharge

d. Denominator in the calculation of proportion = number of patients discharged alive (n=819)

e. Patients lost to follow-up were considered as cured

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Table 4 : Adverse events and clinical outcome by age category in 1029 patients with second-

stage HAT treated with melarsoprol in Kiri SSTC, southern Sudan. Data expressed as n (%).

0 – 5 years old

n = 61

6 – 15 years old

n = 230

> 15 years old

n = 738

P-valuea

Adverse events

All 42 (69) 178 (77) 548 (74) 0.36

Severe 28 (46) 130 (57) 339 (46) 0.02

Typeb

- Headache 12 (22) 101 (45) 318 (44) 0.006

- Fever 25 (45) 103 (47) 216 (30) <0.001

- Tremor 1 (2) 47 (22) 132 (19) 0.004

- Polyneuropathy 4 (8) 15 (7) 93 (13) 0.03

- Bullous rash 1 (2) 1 (1) 4 (1) 0.47

- Macular rash 15 (27) 17 (8) 29 (4) <0.001

- Skin necrosis 2 (4) 2 (1) 1 (0) 0.001

- Diarrhea 8 (15) 26 (12) 86 (12) 0.81

- Hypotension 0 (0) 2 (1) 6 (1) 0.79

- Hypertension 0 (0) 4 (2) 45 (6) 0.007

- Jaundice 3 (6) 3 (1) 4 (1) 0.002

- Melarsoprol reaction 23 (39) 94 (41) 214 (29) 0.001

- ES (all grades) 2 (3) 24 (10) 95 (13) 0.07

Grade of ES 0.02

- Grade 1 0 (0) 1 (0) 34 (5) 0.003

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- Grade 2 0 (0) 14 (6) 38 (5) 0.16

Case-fatality of ES 2 (100) 9 (38) 23 (24) 0.03

Outcome

Issue at discharge 0.93

- discharged alive 58 (95) 219 (95) 713 (96)

- in-hospital death 3 (5) 11 (5) 25 (3)

Attendance to follow-upc 44 (77) 191 (88) 557 (79) 0.01

Follow-up outcomed 0.21

- Definite or probable cure 43 (74) 182 (83) 538 (75)

- Relapse 1 (2) 9 (4) 19 (3)

- Death 1 (2) 2 (1) 11 (2)

Treatment failuree 5 (8) 22 (10) 55 (8) 0.59

a. P-value measured by Pearson Chi-square

b. Number of missing data varying with type of adverse events

c. Definition: > 1 control within 24 months after discharge

d. Denominator in the calculation of proportion = number of patients discharged alive (n=990)

e. Patients lost to follow-up were considered as cured

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