Human toxoplasmosis in Europe. Parasitology, Paris Descartes University, Cochin Hospital, Paris, France

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1 Human toxoplasmosis in Europe Prof Jean Dupouy-Camet Parasitology, Paris Descartes University, Cochin Hospital, Paris, France

2 Toxoplasma gondii, discovered in 1908, by Nicolle at Institut Pasteur de Tunis, from gondis captured in the Matmata region

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4 Toxoplasmosis : a worldwide zoonosis

5 Dupouy-Camet, 1993

6 A decreasing prevalence in Europe > 60 % % % % < 10 % Pappas, 2009 in press

7 A plastid organelle in Toxoplasma Fichera & Roos, Nature, 1997, 390,

8 Life cycle elucidated in the 1970s

9 J Exp Med Oct 1;132(4):636-62

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11 Polymorphism of Toxoplasma isolates : two main lineages in Europe

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13 Additional lineages in America and genetic recombinations Canada ER1 - ER11 : Isolates from ocular lesions

14 Brazil Europe

15 Variable virulences in mice

16 Cycle

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18 Sources of infection in Europe

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20 Risk factors to acquire toxoplasmosis during pregnancy (France) Case control study (80 controls, 80 cases) Beef : raw or rare OR = 5.8 (2.4-17) Mutton : raw or rare OR = 5.2 (2-17.3) Raw meat out home OR = 8.3 ( ) Raw vegetables out home OR = 2.8 ( ) Cat at home OR = 2.1 ( ) NS Baril et al., Scand J Infect Dis, 1999, 31:305

21 Clinical signs & symptoms

22 Most of the time : inapparent infections Sometimes symptomatic Acquired infection fever «chronic fatigue syndrom» Lymph nodes enlargement +/- blood monocytosis Congenital Infection Chorioretinitis Hepato-splenomegalia Brain calcifications, hydrocephalus, microcephalia, Symptomatic in immunosuppressed Brain abcess Disseminated forms

23 First cases of congenital toxoplamosis described a long time ago Arch Dis Child June; 24(118):

24 Hydrocephalus and strabism

25 Brain calcifications

26 Microphthalmy from Couvreur Severe congenital toxoplasmosis with drainage of hydrocephalus from Ho-Yen

27 Ho-Yen & Joss, 1992

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29 Decrease of cerebral toxoplasmosis linked to AIDS due to HAART (France) 6000 HAART AIDS CT

30 Still a problem during heart, lung and bone marrow transplantation Particularly when the receiver is seronegative and the donor seropositive Toxoplasmosis can be reactivated by immunosuppression in seropositive receiver

31 Ocular toxoplasmosis Frequent cause of posterior uveitis one OT out of 1000 patients seen in an ophthalmologic outpatients clinic (Dupouy-Camet et al.,1995) Clinical signs & prognosis depend on inflammatory reaction and localization Active lesion Scar

32 Against the dogma : acquired infections could account for most cases of OT Am J Opht cases : 23.5% acquired, 14.6% congenital 61.9% of unknown origin

33 Screening of congenital toxoplasmosis Programs depend on the national prevalences Compulsory prenatal screening Partial prenatal screening Neonatal screening Partial neonatal screening No screening (choice) No screening No data From Voute- Selod, 2005

34 Prevention 1.Primary prevention avoids the development of a disease. 1.Secondary prevention aims at early disease detection, increasing opportunities to prevent progression of the disease. 1.Tertiary prevention reduces the negative impact of an already established disease

35 Prevention for toxoplasmosis 1.Primary prevention : hygienic rules 1.Secondary prevention : serologic screening, spiramycin, antenatal & neonatal diagnosis 1.Tertiary prevention : antenatal and post natal treatment

36 Type of prevention of congenital toxoplasmosis I, II & III Partial I, II & III I & III partial I & III I partial I No data From Voute- Selod, 2005

37 France A national program of prevention implemented 30 years ago by Desmonts, Chevallier, Garin, Couvreur Observation of numerous congenital cases Based on serologic surveillance & spiramycin

38 Program of prevention : laws 1978: mandatory Toxoplasma serology for the medical certificate before wedding 1983: hygienic rules given to unprotected woemn during pregnancy 1985: mandatory Toxoplasma serology at the first prenatal medical exam 1992: mandatory monthly Toxoplasma serology for non protected pregnant women

39 Seroconversion during pregnancy Treatment by spiramycin (3x 3MUI per day) Prenatal diagnosis At least 4 weeks after infection At least at 16 weeks of pregnancy

40 Prenatal diagnosis on amniotic fluid Positive Negative sulfadiazinpyrimetamine or sulfadoxinpyrimetamine Echography every month If severe lesions spiramycin Pregnancy interruption At birth : clinical examination, serology, echography

41 Fetal echography : hydrocephalus and calcifications

42 Fetal echography : hydrocephalus and calcifications Pregnancy interruption

43 Prenatal diagnosis on amniotic fluid First results published by our lab in 1990 & 1992: single copy gene PCR P

44 Our results in 1999

45 Advantages of Real time PCR Amplification and revelation in the same step thus reducing contamination Quantitative Quicker than conventional PCR Development of real-time PCR for detection of Toxoplasma gondii in animal tissues Jauregui et al, 2001

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47 Neonatal diagnosis : Comparative Western-blot M N M N M N M N positive neonatal diagnosis negative neonatal diagnosis

48 Newborn transfontanellar echograpgy : hydrocephalus, calcifications treatment

49 Infected new born Treatment : sulfadoxine pyrimethamine or sulfadiazine pyremethamine during at least 12 months + folinic acid Blood cells counts every month Eye examination every 3 months

50 Facts about toxoplasmosis in pregnant women in France, 2007 pregnancies / year Ab prevalence : 45 % population at risk : 55 % contamination : 0,3 % 1300 Fetal transmisssion : 29 % 380 Declared congenital cases NRC 2007 : 272 cases

51 Evaluation of the french program : major draw backs No snap shot of the epidemiological situation at onset of the program Difficult to evaluate the impact of the program...but severe cases are not seen anymore

52 Public health analysis SYROCOT Thiebaut R, Leproust S, Chene G, Gilbert R. Lancet Jan 13;369(9556):

53 Findings from 26 cohorts «In 1438 treated mothers, weak evidence that spiramycin started within 3 weeks of seroconversion reduced mother-to-child transmission compared with treatment started after 8 or more week» «In 550 infected liveborn infants, no evidence that prenatal treatment significantly reduced the risk of clinical manifestations»

54 Biases - Different european centres - Different evaluators - Different populations.

55 No major incidence of the type of screening on the delay of detection of ocular toxoplasmosis Freeman, K. et al Monthly screening : France Every 3 months : Italy, Austria Neonatal : Poland, Scandinavia

56 However, for some authors, congenital toxoplasmosis should be diagnosed and treated early during pregnancy

57 Compared to spiramycine alone, sulfadiazine + pyrimethamine reduces the IgM prevalence at birth and increase the prevalence of subclinical infections

58 Prenatal treatment decreases transmission level from 72 to 38 % and the incidence of severe sequelae from 20 to 3.5 %

59 Programs of prevention but what about surveillance

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62 Conclusions Is there still a need for screening congenital toxoplasmosis?

63 Frequency of some screened congenital diseases Disease Toxoplasmosis Hepatitis B Syphilis Rubella Hypothyroidism Phenylketonuria Surrenal hyperplasia Incidence / 1000 births < From Ambroise-Thomas et al., 2001

64 Conclusions Is there still a need for screening congenital toxoplasmosis? YES There is a cost : a choice of society

65 Annual cost of the French program of prevention : 80 millions Rafale by Dassault

66 Costs Identification of a severe cas : 0.5 M Additionnal costs for the «whole life» of severely disabled person > 3 millions

67 Costs could be reduced by a minimum program??? Hygienic rules if seronegative when pregnancy is identified Echography at regular intervals (if important lesions : termination) Neonatal screening (if infected newborn, 1 year of treatment)

68 Conclusions Is there still a need for screening congenital toxoplasmosis? There is a cost : a choice of society Slow decrease of the disease : disparition of the parasite?

69 Decreasing seroprevalence from Ancelle et al.2009 Cochin NPS Ile de France NPS France Séroprévalence (%)

70 Prevalence of toxoplasmosis in France (national studies in pregnant women) -a 10 % decrease every 10 years - 0 % in 2050??? Year Origin LNS INSERM Prevalence 63 % 54 % 2003 INSERM-IVS +/ %

71 From the ethical and medical point of view : prevention seems compulsory

72 But economical pressure crisis