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TOXOPLASMOSIS

AN UPDATE
DR. OANA FALUP-PECURARIU MD. PHD.
TRANSILANIA UNIVERSITY FACULTY OF
MEDICINE
CHILDRENS CLINIC HOSPITAL, BRASOV,
ROMANIA

Toxoplasma gondii is a universal infection around


the world and it affects equally all countries.
Its definitive hostis actally is the infected cat and
aquisition of the infection at human is due to
direct contact with the cat, ingestion of tissue
cysts, under-cook or raw live cooked meat.
The disease was discovered in Brazil by Splendore
and by Nicolle and Manceaux in Tunisia in 1908.
Janku describes in 1923 the congenital form of
the disease in an infant with hydrocephalus and
microophalmia.
The main way to aquiere the disease is by
consuming raw foods or contaminated water but
also through laboratory accidents, blood
transfusions, organ transplantation and fetal

First screening programm for toxoplasmosis : in


1988 in New England, followed by the ones in
Denmark, Poland, Brazil
The estimated incidence of the disease is
variable:
0.7/100000 in Sweden
0.8/100000 in Massachusuttes
7.1/100000 in Poland
In Brazil: 5,4/100000 (public sector) ;
20/100000(Private sector)
There are three stages of the disease:
1. tachyzoites in groups or clones
2. bradyzoites in tissue cystes
3. sporozites in oocysts.

Toxoplasmosis cycle of
maturation

ULTRASTRUCTURE OF A
TACHYZOITE

The most challenging problem is how a


pregnant woman aquiered the infection
during preganancy.
Problems with the testing:
- the persistence for lifelong span of
the IgG
- the lack of the ability of IgA, IgE and
IgM to discriminate between acute versus
old infection

The IgG avidity test :


discriminates -past / recently acquired infection
Results are based on the measurement of the
avidity (functional affinity) of toxoplasma-specific
IgG antibodies
Following an antigenic challenge, the antibodies
produced usually have a low average affinity.
During the course of the immune response
maturation of antibody affinity that increases
progressively
Increase in IgG affinity results from an antigendriven B-cell selection process, resulting in an
increase in complementarity of the antigenantibody-binding site.

the avidity tests are helpful primarily to rule out


that a patient's infection occurred within the prior
4 to 5 months
useful in pregnant women
in their first months of gestation who have a
positive test for both IgG and IgM toxoplasma
antibodies
A woman who has a high avidity test result in her
first trimester did not acquire the acute infection
in the preceding 3 months.
Therefore, since her infection was acquired prior
to gestation her fetus is essentially not at risk

new methods for diagnosis of the infection in the


fetus and newborn
usefulness of
Western blots of paired maternal and baby sera
for this purpose
It is important to point out that the method
should always be used in combination with other
serologic tests such as the IgM and IgA ELISA or
ISAGA.
Thus, in the absence of such early diagnosis, it is
critical that all infants at risk be carefully
monitored by repeated testing.

The PCR has been successfully used to diagnose


congenital and ocular toxoplasmosis and
toxoplasmosis in immunocompromised patients.
Prenatal diagnosis of congenital toxoplasmosis is
primarily based on ultrasonography and PCR with
amniotic fluid.
PCR performed from 18 weeks of gestation is
more sensitive, more rapid, and safer than
conventional diagnostic procedures involving
fetal-blood sampling

Mothers with infection during gestation should be


evaluated at birth for the possibility of congenital
toxoplasmosis
Offspring of mothers chronically infected with the
parasite but who are immunologically
compromised (e.g., those with human
immunodeficiency virus infection or those
receiving high-dose immunosuppressive drugs)
should also undergo a thorough diagnostic
workup to rule out the possibility of congenital
toxoplasmosis
Real-time PCR has recently been introduced for
the diagnosis of toxoplasmosis

Women at risk to give birth at newborn with


congenital toxoplasmosis:
are those which are antibody negative
have raw meat practicing cuisine
women which during their pregnancy are travelling
to areas where this are current practices
cat owners are at risk for transmitting the disease.
Transplacental transmission may occur any time
during pregnancy - more common in the later
pregnancy. The severity of the infection is however
inversely linked to the gestational age at which it
occurs.

There are four groups of patients that need better


screening methods and these are:
a. pregnant women who aquiere the infection
during pregnancy
b. fetuses and newborns that are congenitally
infected
c. immunocompromised patients
d. Patients with chorioretinitis

Prospective study of infants born to women who acquired


Toxoplasma infection during pregnancy
FINDING

EXAMINED(n)

Prematurity 210
birth weight <
2500 g
birth weight
25003000 g

210

POSITIVE%
(n)
8(3,8)
5(7,1)

Dysmaturity
(intrauterine
growth
retardation)

13(6,2)

Postmaturity

108

9(8,3)

Icterus

201

20(10)

Hepatosplenomeg
aly

210

9(4,2)

Thrombocytopeni
c purpura

210

3(1,4)

Abnormal blood
count (anemia,
eosinophilia)

102

9(4,4)

Microcephaly 210
11 (5.2)

210

Chorioretinitis
unilateral

210

11(5,2)

34(16,1)

EXAMINED(n)

POSITIVE%
(n)

Hydrocephalus

210

8(3,8)

Hypotonia

210

2(5,7)

Convulsions

210

8(3,8)

Psychomotor
retardation

210

11(5,2)

Intracranial
calcifications on
radiography 210 24
(11.4

210

24(11,4)

Abnormal
ultrasound
examination

49

5(10)

Abnormal computed
tomography scan of
brain

13

11(84)

Abnormal
electroencephalogr
aphic result

191

16(8,3)

Abnormal
cerebrospinal fluid

163

56(34,2)

Microphthalmia

210

6(2,8)

Strabismus

210

11(5,2)

Adverse sequelae with subclinical


infection at birth
SEQUELAE
%
Chorioretinal lesions

86

Unilateral blindness

81

Bilateral blindness

70

Recurrent chorioretinitis

60

Severe, permanent neurologic


sequelae

33

Mentally retarded

14

Sequentially lower IQ scores 86

86

Trimester of
maternal
acquisition

Incidence of
transmission %

Relative severity
of disease

17

severe

II

25

intermediate

III

65

Milder/ asymptomatic

Gestational
age
at maternal
seroconversio
n,
weeks

Risk of
congenital
infection (95%
CI), %

Development
of clinical
signs in the
infected
offspring
(95% CI), %

Risk of
development
of clinical
signs when
infection
status is
unknown,a %

13

6(3-9)

61(34-85)

26

40(33-47)

25(18-33)

10

38

72(60-81)

9(4-17)

Management of Toxoplasma gondii infection during pregnancy. J.G.Montoya et al. CID.


Clinical practice 2008;47:554-566.

What are the major signs of toxoplasmosis


infection?
symptomatic neonatal infection - usually in the
first month and is mainly neurological
during late childhood we may see the sequelae
which are mostly represented by chorioretinitis
Around 40% of the affected children show at CT
scan typical calcifications.
The vast majority of children have however
subclinical disease and the persistence of the
infectious agent will lead to the persistence of the
disease

Mem Inst Oswaldo Cruz. Author manuscript;


available in PMC 2009 August 31.

Clinical signs and symptoms for


toxoplasmosis

Eurico Camargo Neto et al. Newborn screening for congenital infectious diseases. Emerg Inf Dis.
Jun2004;10(6):1069-1073.

The finding of antibodies to toxoplasma in a


pregnant woman does not necesarilly mean that
she has the disease at the very moment.
Between 8-40% of the pregnant women may have
IgG positive for toxoplasma but are not sick.
The IgM antibodies may persist for more than
one year.
20% of pregnant women that present with
lymphadenopaty, fatigue and mononucleousis
like illness and cook with raw meat.
Ulltrasound of the fetus of this women may also
show hydrops fetalis, microcephaly, intracranial
calcifications, hepatosplenomegaly, but definitive
diagnosis may require more complex tests.
In pregnant women demonstration over a three
weeks period of time with growing of IgG serum

For pregnant women

1. All pregnant women should be provided with


information about the prevention of
toxoplasmosis infection
2. Pregnant women who are identified as being at
risk of infection by virtue of clinical findings
(lymphadenopathy, fatigue and mononucleosislike illness), first time in life contacts with kittens
or culinary practices including ingestion of raw
meat should be tested. If a woman is susceptible,
follow-up testing is recommended.
3. When considering the therapy of pregnant
women, expert consultation is recommended to
determine the acuity of infection with regard to
risk of fetal infection.

Jose G Montoya and J S Remington. Management of Toxoplasma Gondii Infection during Pregnancy. Clin
inf dis 2008; 47:554-566

For newborn infants:


The diagnosis should be considered in newborns
with intrauterine growth retardation,
hydrocephalus, microcephalus,
hepatosplenomegaly, hepatitis, petechiae,
thrombocytopenia or esotropia.
Further evidence of infection may be found on
ophthalmological and cranial CT examinations
before laboratory testing.
Serological confirmation of newborn infection
requires detection of positive specific IgM, IgA or
IgE antibodies.
Infection in the mother should be documented
serologically by a reference laboratory
Specific therapy in neonatal infection should be

TREATMENT DECISION

Eurico Camargo Neto et al. Newborn screening for congenital infectious diseases. Emerg Inf Dis.
Jun2004;10(6):1069-1073.

TREATMENT
Anti-parasitic agents that restrict the growth of
actively proliferating parasites, which destroy cells and
tissues, thereby prevent damage to the brain and eye
The combination of pyrimethamine and sulfadiazine is
8-fold more active than either pyrimethamine or
sulfadiazine alone and has been the gold standard to
which other antimicrobial agents alone, and in
combination, have been compared
By the year 1981 the medical community started to
treat congenital toxoplasmosis with pyrimethamine
and sulfadiazine for 1 year given with leukovorin found
to be effective.

Thus in this RCT, there was randomization to a higher


and lower pyrimethamine dose [i.e., change from daily to
3 times a week treatment with pyrimethamine at 2
(lower dose) or 6 (higher dose) months after initiation of
treatment].
This design was to determine whether there might be a
dose response in either efficacy or toxicity and if there
were no major differences and outcomes were
nonetheless improved.
Outcomes with earlier treatment of the mother during
gestation with medicines that cross the placenta and that
were continued through the first year of life appear to be
even better than when treatment is initiated at birth

Interim, cumulative data for evidence of studyrelated adverse events.


COHORT

NO. OF
DEATHS/NO. OF
CHILDREN %

MEAN AGE AT
DEATH IN
YEARS

AGES AT DEATH

RANDOMIZED
TREATMENT 1

3/47 (6.4)

7.3

1.3, 9.9; 10.8

RANDOMIZED
TREATMENT 2

5/38(13)

3.6

0.3; 1.7; 4.5;


5.7,5.8

FEASIBILITY/OB
SERVATIONAL
TREATMEN1

1/14(7)

9.3

9.3

FEASIBILITY/OB
SERVATIONAL
TREATMEN2

2/21(9.5)

2.5

0.5; 4.5

Outcome of treatment for congenital toxoplasmosis 1981-2004; The national collaborative Chicago based congenital
toxoplasmosis study. Clin Infect Dis. Vol42; 10: 1383-94. Rima McLeod et al.

Take home message


Increasing the public health priority of treating
and preventing Toxoplasmainfection could
provide an impetus to development of better
medicines, those with effect on latent parasites
and with less toxicity, less need for monitoring
and less hypersensitivity and vaccines to
prevent this disease.