Toxoplasmosis

Question 1

What is Toxoplasma gondii (TG)?

Answer 1

An obligate intracellular protozoan (parasite)

Question 2

Symptoms of TG

Answer 2

Almost always, no maternal symptoms. Occasionally flu/mononucleosis-like fever, fatigue, rash, head/neck lymphadenopathy.
Rarely, pregnant women will present with visual changes due to chorioretinitis from recently acquired infection or reactivation of chronic infection.

Question 3

What is the definitive host of TG?

Answer 3

The definitive host is the cat (only one that can support both sexual and asexual reproduction).

Question 4

What forms does TG exist in?

Answer 4

1. Trophozoite (invasive form)
2. Cyst (latent form)
3. Oocyst (only in cats: result of sexual reproduction, which occurs in the small intestine of a cat who has eaten outside tissue cysts containing TG)

Question 5

When are cats infectious with TG?

Answer 5

Only during first exposure is the cat infectious, as these oocysts are produced for two weeks and contain infectious sporozoites; the oocysts require one to five days to become infected; after two weeks the cat becomes immune and not infectious. In soil, oocysts can remain infectious for years.

Question 6

How does human infection with TG occur?

Answer 6

Human infection starts with ingestion (from food, water, hands, or insects) of cysts from uncooked/undercooked meat of infected animals (e.g., lamb and mutton) or contact with oocysts from infected cats (who get it from infected mice, etc.) or contaminated soil.

Question 7

What happens when a pregnant woman ingests TG oocysts?

Answer 7

The infected oocysts become infective inside the pregnant woman in 4 to 10 (average 7) days, leading to parasitemia. Eventually, TG can infect and live forever in striated muscle or brain.

Question 8

Does congenital TG occur in women infected prior to conception?

Answer 8

Only a very few cases of congenital toxoplasmosis transmitted by mothers who were infected prior to conception have been reported; they can be attributed to either reinfection with a different strain or to reactivation of chronic disease. This reactivation is very rare, but can occur especially in an immunocompromised woman. Immunocompetent women with prior toxoplasmosis can be reassured that the risks to the subsequent fetus/neonate are miniscule, especially >9 months after infection.

Question 9

Of congenitally infected fetuses (PCR+ amnio for TG), what percent have subclinical infection? What percent have fetal/childhood illness?

Answer 9

• 74% to 81% manifest only subclinical infection (only serologically positive)
• 19% to 26% have fetal/childhood illness even if they received treatment

Question 10

What percentage of fetuses of primary TG-infected mothers are affected?

Answer 10

7%

Question 11

Fetal/neonatal TG disease is more common if maternal infection occurs in what trimester?

Answer 11

3rd trimester

Question 12

Fetal or neonatal TG disease is more severe if maternal infection occurs in what trimester?

Answer 12

1st trimester. But there is less than a 1/1000 chance of fetal infection if GA is less than 4w at time of maternal infection.

Question 13

Probability of congenital TG if maternal infection occurs preconception

Answer 13

1%

Question 14

Probability of congenital TG if maternal infection occurs in 1st trimester

Answer 14

10-25%

Question 15

Probability of congenital TG if maternal infection occurs in 2nd trimester

Answer 15

30-55%

Question 16

Probability of congenital TG if maternal infection occurs in 3rd trimester

Answer 16

60-80%

Question 17

Signs of fetal TG infection

Answer 17

Ventriculomegaly (75%)
Placentomegaly (32%)
Hepatomegaly (12%)
Ascites (15%)
Intracranial calcifications (18%)
Hydrocephalus (4%)
Microcephaly (5%)
HSM (4%)

Question 18

Neonatal signs of TG infection

Answer 18

Chorioretinitis (26%)
Deafness
Decreased IQ
Subsequent blindness, seizures, neuropsychomotor delay

Question 19

Complications of congenital TG infection

Answer 19

PTB
Not IUGR, when seroconversion occurs before 20w
Stillbirth/neonatal death is rare

Question 20

Prevention of congenital TG

Answer 20

• Avoid raw or undercooked meat (or eggs) of any origin
• Avoid contact with raw meat or soil
• Wash fruits and vegetables before eating
• Cats: Avoid changing cat litter. Hand-wash after handling cat. Do not let cats outside the house (could eat infected mice). No stray cats in the house. No feeding raw meat to cats. Avoid raw milk.

Question 21

When do IgG TG antibodies appear?

Answer 21

Usually within 2w of infection, persist indefinitely

Question 22

IgM in the diagnosis of recent TG infection

Answer 22

IgM antibodies are considered to be a sign of recent infection and can be detected by enzyme immunoassays (EIAs) or an immunosorbent agglutination assay test (IAAT) within two weeks of infection. They often remain positive for up to one to two years.

Question 23

What is the gold-standard test for TG infection?

Answer 23

The Sabin–Feldman dye test (SFDT) is still considered the “gold standard”. It detects the presence of anti-TG- specific antibodies (total Ig). The absolute antibody titer is also important: values over 250 IU/mL are considered highly suggestive of recent infection.

Question 24

How does IgG avidity aid in the diagnosis of TG infection?

Answer 24

IgG avidity testing is based on the increase in functional affinity (avidity) between TG-specific IgG and antigen over time, as the host immune response evolves. Pregnant women with high avidity antibodies are those who have been infected at least three to five months earlier.

Question 25

Diagnosis of maternal TG infection

Answer 25

Maternal infection is diagnosed by sending maternal serology to a reference laboratory (http://www.pamf.org/serology/clinicianguide.html). It is best to make the diagnosis based on two different serum specimens collected at least four weeks apart. Usually, the reference laboratory reports many serologic results, with a high possibility of infection if there is:

1. Seroconversion during pregnancy;
2. Increase in both specific IgG titer (>3-fold) and dye test (>3-fold)
3. Presence of specific IgM and dye test >/= 300 IU/mL.

Question 26

How is fetal congenital TG infection diagnosed?

Answer 26

Fetal congenital infection is diagnosed by

• AF PCR: Spec and PPV are close to 100%; sens is around 70% to 80%, but is best when maternal infxn occurs btw 17w and 21w.
• Real-time PCR - sens of 92%, NPV of 98%, and may not be as GA dependent as conventional PCR.
• Negative AF PCR does not always completely rule out congenital infection.
• AF PCR should obviously be done after 15 weeks.
• Ultrasound can also aid in diagnosis of fetal infection, but it has very poor sensitivity and specificity.

Question 27

Treatment of TG if maternal infxn diagnosed

Answer 27

• If maternal infection is detected, counsel regarding the risks, along with possibility of termination (esp 1st trimester), and management.
• If maternal infection is confirmed by a reference lab, start spiramycin 3 to 4 g/day (1 g q 8 hrs). This is available in the United States only by the FDA when Palo Alto serology is positive.
• Spiramycin concentrates in the placenta, and therefore may not be reliable for treatment of infection in the fetus.

Question 28

Treatment of congenital TG in the fetus

Answer 28

• If + AF PCR, start sulfadiazine (initial dose of 75 mg/kg, followed by 50 mg/kg q12h w/ max of 4 g/d), pyrimethamine (50 mg po q 12h for two days followed by 50 mg/d), and folinic acid (leucovorin) 10 to 20 mg with each dose of pyrimethamine (decreases bone marrow toxicity) and one week after completion of pyrimethamine.
• Length of therapy is controversial, has varied from a minimum of 28 days (with 1⁄2 dose until term), versus continuing tx as is until term.
• Treatment with pyrimethamine and sulfadiazine to prevent fetal infection is contraindicated during the first trimester (pyrimethamine is teratogenic), but at this time sulfadiazine can be used alone.
• This treatment should be stopped in the last few weeks of pregnancy.
• Other drugs such as spiramycin (3–4 g/day 3–4 weeks) are recommended in certain circumstances. Spiramycin is used to prevent placental infection; it is used in European countries, but in the United States it is not approved by the FDA. Treatment decreases complications of TG, but possibly not fetal infection.

Question 29

How successful is treatment of congenital TG in the fetus?

Answer 29

• It is estimated that for every three congenitally infected fetuses that are treated, one case of serious neurological sequela is prevented.
• In one study, fetuses/neonates treated and subsequently followed for 12 to 250 months had a 17% rate of congenital TG, with 74% of the children asymptomatic, 26% developing chorioretinitis (72% peripheral and unilateral), and all except one child having age-appropriate neurological and intellectual development.

Question 30

TG infection in the immunocompromised patient

Answer 30

Dysfunction of the CNS is the most common manifestation of infection. Findings typically include encephalitis, meningoencephalitis, and intracerebral abscess. Pneumonitis, myocarditis, and generalized lymphadenopathy also occur commonly.