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
infection occurs through hematogenous contamination
through the placenta.
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 antigen-driven B-cell
selection process, resulting in an increase in complementarity
of the antigen-antibody-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) POSITIVE%(n) EXAMINED(n) POSITIVE%(n)

Prematurity 210 210 Hydrocephalus 210 8(3,8)

birth weight < 2500 g 8(3,8)
birth weight 2500–3000 5(7,1)
g
Hypotonia 210 2(5,7)
Dysmaturity 13(6,2)
(intrauterine growth
retardation)
Convulsions 210 8(3,8)

Postmaturity 108 9(8,3)

Psychomotor retardation 210 11(5,2)

Icterus 201 20(10) Intracranial calcifications 210 24(11,4)

on radiography 210 24
(11.4
Hepatosplenomegaly 210 9(4,2)
Abnormal ultrasound 49 5(10)
examination
Thrombocytopenic 210 3(1,4)
purpura Abnormal computed 13 11(84)
tomography scan of brain
Abnormal blood count 102 9(4,4)
(anemia, eosinophilia) Abnormal 191 16(8,3)
electroencephalographic
result
Microcephaly 210 11 210 11(5,2)
(5.2)
Abnormal cerebrospinal 163 56(34,2)
fluid
Chorioretinitis 210
unilateral 34(16,1) Microphthalmia 210 6(2,8)
bilateral 12(5,7)
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 Incidence of transmission Relative severity of

acquisition % disease
I 17 severe
II 25 intermediate
III 65 Milder/ asymptomatic
Gestational age Risk of congenital Development of Risk of
at maternal infection (95% CI), clinical development
seroconversion, % signs in the of clinical signs
weeks infected when
offspring (95% CI), infection status is
% unknown,a %
13 6(3-9) 61(34-85) 4

26 40(33-47) 25(18-33) 10

38 72(60-81) 9(4-17) 7

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 titer is the best
demonstrating test.
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 mononucleosis-like 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.
 4.The latter can be confirmed in tertiary care centres by
amniocentesis and/or cordocentesis, and serial ultrasound
examination
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 undertaken in
consultation and collaboration with an expert in the field.
 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 study-related adverse
events.

COHORT NO. OF DEATHS/NO. MEAN AGE AT DEATH AGES AT DEATH

OF CHILDREN % IN YEARS

RANDOMIZED 3/47 (6.4) 7.3 1.3, 9.9; 10.8

TREATMENT 1

RANDOMIZED 5/38(13) 3.6 0.3; 1.7; 4.5; 5.7,5.8

TREATMENT 2

FEASIBILITY/OBSERV 1/14(7) 9.3 9.3

ATIONAL
TREATMEN1

FEASIBILITY/OBSERV 2/21(9.5) 2.5 0.5; 4.5

ATIONAL
TREATMEN2

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 Toxoplasma infection 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.