schistosomiasis: in the€¦ · serum schistosoma dna (pcr) 100 increased diagnostic yield with...

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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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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


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


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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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


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)


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


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%)





pain


ova in feces/urine



Symptoms 19‐51d (94%)

w4‐w8 (62%)





pain


ova in feces/urine




w4‐w8(62%)

Ab: w7‐w14 (50%)





pain


ova in feces/urine




w4‐w8(62%)

Ab: w7‐w14 (50%)

No eggs (0%)

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pain


ova in feces/urine




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)


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



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


0 2 4 hours

PZQ 20mg/kg

PZQ 20mg/kg




D1 D2 D3

Methylprednisolone 0.5 mg/kg/daycycle of 3 days to repeat if recurrence

All infected


0 2 4 hours

PZQ 20mg/kg

PZQ 20mg/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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schistosomiasis: in the€¦ · serum schistosoma dna (pcr) 100 increased diagnostic yield with...

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