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Schistosomiasis: Filling in the Gaps
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EMMANUEL BOTTIEAU
No state of Conflict of Interest exists between our two parties, nor between us and a third party, for this
Workshop.
FEDERICO GOBBI
ACKNOWLEDGEMENTS: JAN CLERINX, LIESELOTTE CNOPS
Outline
Gaps in diagnosis and treatment of acute schistosomiasis
E. Bottieau
Gaps in diagnosis and treatment of chronic schistosomiasis
F. Gobbi
VO, Belgian, 30 years; consultation ITMA on May 14, 2012
No medical history
Back from Guinée since May, 1st (9 months for MSF)
Recent problems
End of March: fever: Paracheck (HRP2 RDT) positive for P. falcmalaria; start Coartem (3 days); better
Fever again 2 weeks later: RDT neg; suspicion of typhoid fever: ciprofloxacine 5 days; better
Fever again 2‐3 weeks later: Coartem empirically; not really better: persistance of fever and onset of dry cough (at night)
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VO, Belgian, 30 years; consultation ITMA on May 14, 2012
Better since a few days (after being back in Belgium)
Comes for a checkup
Additional information
No contact with sick people
No sexual risk
Did swim in a river near Gueckedou (in March); took praziquantelimmediately after swimming
Did swim again in a waterfall pool near Kindia (Mid‐April)
Took mebendazole preventively after return
Kindia
Guéckédou
Voile de la Mariée , Kindia, Guinée
VO, Belgian, 30 years; consultation ITMA on May 14, 2012
Leucocytes 57,500 (nl < 11,000/µL)
Eosinophils 44,620 (77.6%)
C‐RP 13.5 (nl < 10 mg/L)
LDH: 1,119 (nl < IU/L
IgE: 1,767 (nl < IU/L
HRP2‐based RDT: positive
pan LDH‐based RDT: positive
Blood micrsocopy: negative
Blood results
VO, Belgian, 30 years; consultation ITMA on May 14, 2012
Urine examination
Normal urinalysis
Culture neg
Parasite microscopy neg
Feces examination
Charcot‐Leyden crystals +++
Cysts of Entamoeba dispar/histolytica(PCR: E. dispar)
Giardia antigen test positive
Eggs of Schistosoma mansoni (30/gr)
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VO, Belgian, 30 years; consultation ITMA on May 14, 2012
P. falciparum: 1/320
Schistosoma ELISA: positive
Schistosoma IHA: 1/640 (nl < 1/160)
S. stercoralis (and other relevant serologies) negative
Serology
Molecular workup PCR + for Schistosoma sp. in stool and blood (121 bp)
Survey performed March 2019: response by 34 “TropNet” experts
Survey performed March 2019: response by 34 “TropNet” experts
VO, Belgian, 30 years; consultation ITMA on May 14, 2012
Diagnoses
Recent P. falciparum malaria (adequately treated)
Acute schistosomiasis/Katayama (S. mansoni)
Giardiasis (asymptomatic)
Treatment
Praziquantel (PZQ) 60 mg/kg/day for 2 days (3‐3)
Medrol 32 mg‐16‐16‐8‐8‐8‐8
(new malaria testing in case of fever recurrence)
VO, Belgian, 30 years; consultation ITMA on May 14, 2012
Diagnoses
Recent P. falciparum malaria (adequately treated)
(Resolved) Katayama fever/Acute schistosomiasis (S. mansoni)
Giardiasis (asymptomatic)
Evolution
No clinical exacerbation; no recurrence of fever
07/06: control (GP): 3,546 eosinophils
25/06: second PZQ course (1 day)
31/08 control (ITMA): 960 eosinophils; parasito neg
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Schistosomiasis: recent cases/clusters in travelers (ITMA)
Clerinx J. Trav Med Infect Dis 2011
2008; n=1
2012; n=1
2009; n=13
2012; n=22
2008; n=1
2011; n=9
2008; n=48
2017; n=34
Schistosomiasis: life cycle and timing of early events
Ross A et al. Lancet Infect Dis 2007
Katayama fever (ITMA 2000‐4): clinical features (n=23)
Bottieau et al. J Infect 2006
n %
Myalgia 17 74
Headache 13 57
Cough 12 52
Abdominal symptoms 10 43
High fever (> 39°C) 8 35
Eosinophilia 21 91
Recurrence of symptoms 5 22
Little specificity of presenting features, except eosinophilia
Katayama fever (ITMA 2000‐4): diagnosis at presentation
Bottieau et al. J Infect 2006
%
Egg detection 22
Serology (both IHA and ELISA) 26
Serology IHA alone 26
Serology ELISA alone 0
At least one positive test 65
Low sensitivity of conventional tests even when combined
Katayama fever (cluster 2009 Rwanda) diagnosis (n=13)
Clerinx J et al. J Travel Med 2011
%
Egg detection 69
Serology (both IHA and ELISA) 77
At least one positive test 85
Serum Schistosoma DNA (PCR) 100
Increased diagnostic yield with molecular assay
Schistosoma real‐time PCR at ITM (research only)
‘genus’ PCR (28S rRNA) Cnops et al., 2012Stool (1g) and urine (300µl); not on serum
detection of all species (Sm, Sh, Si, Sj, Smek, no differentiation)
Sm1‐7 PCR Wichmann et al., 2009Serum (2ml=> 1ml=> 400µL) (whole blood) (all other clinical samples)
S. mansoni complex: highly frequent tandem repeat
Dra1 PCR Cnops et al., 2013
Serum (2ml=> 1ml=> 400µL) (whole blood) (all other clinical samples)
S. haematobium complex: highly frequent tandem repeat
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N eosino/µl ELISA HAI fEPG PCR Ct PCR
1 5400 p 320 30 p 282 2090 n 320 120 p 27
3 2640 n n 10 p 30
4 14150 p 640 40 p 29
5 1150 n n n p 35
6 2860 p n 20 p 31
7 14270 p 320 60 p 30
8 11120 p 160 10 p 29
9 1960 p 320 n p 32
10 1290 n n n p 36
11 1210 p n 10 p 32
12 2120 p n n p 27
13 1700 p 320 10 p 35
Rwanda cluster 2009:Real‐Time PCR (Sm1‐7) in serum in acute schistosomiasis with S.mansoni
Time from exposure to diagnosis: 54 to 96 days
PCR promising tool forearly diagnosis
French male, 63 years; consultation Bordeaux June 5, 2012
Trip (one month) to Ivory Coast
Single exposure in a lake on May, 1st
Fever on May, 25th; eosinophilia on May, 29th
On June 5, Bordeaux: fever with no other symptom
Eosinophilia: 1,410/£L (19%)
Serology Schistosoma sp IHA and ELISA neg
Microscopy feces/urine: neg
Trip to Cameroon (June, 8) against medical advice
Development of transverse myelitis; repatriated with paraplegia one monthlater; incomplete recovery despite steroids and praziquantel
X, French, 63 years; consultation Bordeaux June 5, 2012
T2‐weighted sequence: intramedullary contrast
enhancement of the conus medullaris (1a and 1b)
T1‐weighted sequence: heterogeneously enhancing lesion of the conus medullaris with irregular enhancement
extended on the spinal roots of the cauda equina following
intravenous gadolinium injection (2a and 2b)
Case report: early neuroschistosomiasis in a traveler
Bonnefond S et al. J Int J Infect Dis 2019
Earlier diagnosis with molecular assay
Sm1‐7 PCR serum + Sm1‐7 PCR serum +
IW, Belgian, 30 years; consultation ITMA on Jan 26, 2017
No medical history
Back from South Africa (North of Kwazulu‐Natal) since Jan 5
Fever and cough since a few days
Two children have the same symptoms (since 3‐10 days)
Referred by GP because of eosinophilia (760/µL)
IW, Belgian, 30 years; consultation ITMA on Jan 26, 2017
Stay in Eco‐Lodge in South Africa (from 26th December to 5th of January 2017
Group of 8 Belgian families; 34 persons in total
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Cluster of 34 Belgian travelers, exposed to Witrivier
Exposure to Witrivier (uMhkunyana River)
2‐5 Jan, 2017
Cluster of 34 Belgian travelers, exposed to Witrivier
Swimmers‘ itch 16 (47)
Any acute symptom 32 (94)
Among persons with symptoms (n= 32)
Fever 22 (69)
Headache 22 (69)
Muscle ache 17 (53)
Cough 16 (50)
Abdominal pain 14 (44)
Diarrhea 5 (15)
Onset of symptoms 19 – 41 days, (median 25 days)
N (%)
33 persons first seenbetween D27 and D37 (median D29)
One person first seenat D50
Time line acute schistosomiasis: 34 travellers
w1 w2 w3 w4 w5 w6 w7 w8 w9 w10 w11 w12 w13 w14 w15 w16 w17 w18 w19
Month 1 Month 2 Month 3 Month 4 Month 5
exposure coughfeverabdominal
pain
hypereosinophilia seroconversion
ova in feces/urine
incubation period (up to 3 to 8 weeks)
prepatent period (up to 4 to 12 weeks)
Symptoms 19d‐51d (94%)
Time line acute schistosomiasis: 34 travellers
w1 w2 w3 w4 w5 w6 w7 w8 w9 w10 w11 w12 w13 w14 w15 w16 w17 w18 w19
Month 1 Month 2 Month 3 Month 4 Month 5
exposure coughfeverabdominal
pain
hypereosinophilia seroconversion
ova in feces/urine
incubation period (up to 3 to 8 weeks)
prepatent period (up to 4 to 12 weeks)
Symptoms 19‐51d (94%)
w4‐w8 (62%)
Time line acute schistosomiasis: 34 travellers
w1 w2 w3 w4 w5 w6 w7 w8 w9 w10 w11 w12 w13 w14 w15 w16 w17 w18 w19
Month 1 Month 2 Month 3 Month 4 Month 5
exposure coughfeverabdominal
pain
hypereosinophilia seroconversion
ova in feces/urine
incubation period (up to 3 to 8 weeks)
prepatent period (up to 4 to 12 weeks)
Symptoms 19d‐51d (94%)
w4‐w8(62%)
Ab: w7‐w14 (50%)
Time line acute schistosomiasis: 34 travellers
w1 w2 w3 w4 w5 w6 w7 w8 w9 w10 w11 w12 w13 w14 w15 w16 w17 w18 w19
Month 1 Month 2 Month 3 Month 4 Month 5
exposure coughfeverabdominal
pain
hypereosinophilia seroconversion
ova in feces/urine
incubation period (up to 3 to 8 weeks)
prepatent period (up to 4 to 12 weeks)
Symptoms 19d‐51d (94%)
w4‐w8(62%)
Ab: w7‐w14 (50%)
No eggs (0%)
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Time line acute schistosomiasis: 34 travellers
w1 w2 w3 w4 w5 w6 w7 w8 w9 w10 w11 w12 w13 w14 w15 w16 w17 w18 w19
Month 1 Month 2 Month 3 Month 4 Month 5
exposure coughfeverabdominal
pain
hypereosinophilia seroconversion
ova in feces/urine
incubation period (up to 3 to 8 weeks)
prepatent period (up to 4 to 12 weeks)
Symptoms 19d‐51d (94%)
w4‐w8(62%)
Ab: w7‐w14 (50%)
No eggs (0%)
PCR on serum (100%))
Cluster of 34 Belgian travelers, additional testing (LUMC)Pre‐treatment (PZQ) Posttreatment (PZQ)
Tests N/n (%) W4‐5 N/n (%) W 7‐8 N/n (%) W 13‐14
Eosinophils > 750/µL 12/33 (36) 22/34 (65) 3/34 (9)
Schisto ova urine/feces 0/33 (0) 0/34 (0) 0/34 (0)
Schisto IMT ELISA 0/32 (0) 12/34 (35) 10/34 (32)
Schisto IMT IHA 3/32 (9) 0/34* (0) 0/34* (0)
Schisto LUMC IFA 13/33 (39) 20/31 (65) 25/34 (74)
PCR Dra1 24/33 (73) 30/34 (88) 24/34 (71)
UCP‐CAA serum LUMC 30/33 (91) 26/31 (84) 1/34 (3)
Cluster of 34 Belgian travelers, exposed to Witrivier
Very poor performance of conventional methods
Microscopy: 0% sensitive
Serology: 33% sensitive;
Molecular assay (Dra1): 100% sensitive
Genotyping: hybrid S. haematobium / S. matthei
Circulating anionic antigen (CAA): promising for early diagnosis
Schistosomiasis in the Phongola Basin
Swaziland
uPhongolo
Mimi Moya Lodge
Human and cattle schistosome species:S.haematobiumS.mattheei (cattle)S.mansoni (rare!)
In humans, hybrids have been describedof S.haematobium and S.mattheei
Schistosome intermediate hosts:‐Bulinus africanus group: Bulinus globosus, Bulinus africae (predominant mollusks)‐Biomphalaria pfeifferi (patchy distribution)
Frequency and possible consequences of hybridization between Schistosoma haematobium and S. mattheeiin the Eastern Transvaal Lowveld.Kruger FJ. J Helminthol. 1990 Dec;64(4):333‐6.
A survey was conducted at a locality in the Eastern Transvaal Lowveld where the prevalence of human infection with the bovine parasite, Schistosoma mattheei, is relatively high. It was found that, when compared to the number of S. haematobium eggs released into the environment, the number of S. mattheei eggs, with enclosed hybrid miracidia, is small. The consequences of backcrossing between the hybrids and S. haematobium was considered; a mathematical model indicated that a high percentage of the S. haematobium population should contain a small proportion of S. mattheei genes. The results indicate that it is highly unlikely that the two species will evolve into a single species, neither does it seem that the virulence of the parental species will be influenced.
Acute schistosomiasis, principles of treatment
Control of hypersensitivity symptoms: anti‐inflammatory drugs
Preference to steroids
But no solid data on optimal timing, dosage, duration, in particular in children
Antiparasitic treatment: praziquante (PZQ), but
Little activity on larval stages
Risk of early ovideposition (early neuroschistosomiasis)
Risk of clinical exacerbation, and drug interaction with steroids
No evidence of usefulness for acute schistosmiasis in non‐immune travelers
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Schistosomiasis treatment: praziquantel (PZQ) 40 mg/kg
Different PZQ dosagesZwang J. PLoS NTD 2014)
Single dose 40 mg/kg(Zwang J Paras & Vectors 2017)
Cure rate: 75%Egg reduction rate:
85‐95%
Schistosomiasis treatment: adverse event PZQ
Zwang J & Olliaro PL. PLoS NTD 2014
Assessed in > 12,000 subjects Up to 56% (95%CI 47‐68) Light to moderate
Praziquantel forever ? Massive use in “prevention”
WHO. Wkly Epidemiol Rec 2018
Effective
Safe
Cheap
Praziquantel: little effect on larvae
Bergquist R. Trop Med Infect Dis 2018
Almost no effect up to 5‐6 weeks after infection
Praziquantel
Artemisinin
Acute schistosomiasis, early ovideposition (6 weeks?)
Clerinx J et al. Emerg Infect Dis 2006
Boy with left‐sidedhemiparesis and slurredspeech 8 weeks after
exposure
Acute schistosomiasis, clinical exacerbation after PZQ
In up to 50% of the patients
(Bottieau E et al. J Infect 2006)
Sometimes impressive
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Acute schistosomiasis, praziquantel treatment
C max: 1.5h after ingestion; half‐life: 0.8 to 1.5 hours!
Therapeutic effect 4 to 10 h after single dose
Metabolization in inactive derivatives: CYP450
Urinary excretion (70% in < 24h), no nephrotoxicity
Parasite load reduction of single dose PZQ 40mg/kg: > 80%
PZQ concentration when steroids are given concomitantly
If given in fractioned doses: a 4 to 6 h interval is recommended
SA cluster of acute schistosomiasis, treatment at week 4‐5
Methyl‐prednisolone0.5mg/kg
Methyl‐prednisolone0.5mg/kg
Methyl‐prednisolone0.5mg/kg
D1 D2 D3
for symptomatic patients cycle of 3 days
to repeat if recurrence of symptoms
32/34 were symptomatic21/34 were sick enough to be given steroids
15/21 (73%) needed 1 cycle
6/21 (27%) needed 2(4) or 3(2) cycles
Only ifsymptoms
SA cluster of acute schistosomiasis, treatment at week 6‐7
0 2 4 hours
PZQ 20mg/kg
PZQ 20mg/kg
Methyl‐prednisolone0.5mg/kg
Methyl‐prednisolone0.5mg/kg
Methyl‐prednisolone0.5mg/kg
D1 D2 D3
Methylprednisolone 0.5 mg/kg/daycycle of 3 days to repeat if recurrence
All infected
SA cluster of acute schistosomiasis, treatment at week 6‐7
0 2 4 hours
PZQ 20mg/kg
PZQ 20mg/kg
Methyl‐prednisolone0.5mg/kg
Methyl‐prednisolone0.5mg/kg
Methyl‐prednisolone0.5mg/kg
D1 D2 D3
All infected21/34 revovered immediately
9/34 (26%) had mild symptoms of short duration (< 6h)4/34 (12%) developed fever
3/34 (9%) needed a second (2) or a third (1) steroid cycle
Acute schistosomiasis, proposed “ITMA” treatment
Praziquantel 20 mg/kg at hour 0 and at hour 2 Followed at hour 4 by methylprednisolone 0.5 mg/kg/day for 3 days(to repeat if necessary)
If diagnosis made BEFORE week 6 (post‐exposure/infection)
ONLY in case of symptoms
If diagnosis made AFTER week 6 (post‐exposure/infection)
Methylprednisolone 0.5 mg/kg/day for 3 days(to repeat if necessary)
+ Praziquantel 40 mg/kg single dose at week 12
Acute schistosomiasis, SA cluster in ITMA
Lessons learned
Early symptomatic schistosomiasis (< 6 weeks): short course of steroidsis sufficient most of the time
From week 6 onwards single dose praziquantel combined with steroids
prevent acute symptoms
Question to resolve
Single dose praziquantel: sufficient ?
Timing for repeated dose ?
No risk of neuroschistosomiasis before week 6 ?
Treatment dependent of parasite load ?
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Schistosomiasis treatment: artemisinins ?
• More effective on larval
stages/juvenile worms
• Higher efficacy ART‐PZQ
compared to PZQ alone
• More effective than placebo
in chemoprophylaxis
Perez del Villar. PLoS ONE 2012
Schistosomiasis treatment: other drugs clinically tested
Bergquist R. Infect Dis Poverty 2016
Schistosomiasis treatment: alternative drugs summary
Thanks!
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