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Episode #39 – Curious Congenital Conundrums – Seal of Approval

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Summary

Drs. Ella Dzora and Jason Brophy discuss a case of congenital toxoplasmosis in the second case of the Febrile “Curious Congenital Conundrums” series.

Table of Contents

Credits

Hosts: Ella Dzora, Sara Dong

Guest: Jason Brophy

Writing: Justin Penner

Producing/Editing/Cover Art/Infographics: Sara Dong

Our Guests

Guest Consultant:

Dr. Jason Brophy

Twitter

Dr. Jason Brophy is a pediatric infectious diseases specialist and researcher at the Children’s Hospital of Eastern Ontario, and an Associate Professor of Pediatrics at the University of Ottawa. His research and clinical interests are pediatric HIV and congenital infections. He also works as a Pediatric HIV Clinical Advisor with the Clinton Health Access Initiative (CHAI), supporting the uptake of optimal pediatric HIV care in West-Central Africa and Southeast Asia.

Guest Co-Host:

Dr. Ella Dzora

Twitter

Dr Ella Dzora is a paediatric Registrar in South Yorkshire, England. She has an interest in Infectious Diseases and Global Health, particularly migrant health.

Culture

Polio: An American Story

David Oshinsky

Won a Pulitzer Prize!

Plagues Progress

Arno Karlan

Burns Night!

Consult Notes

Case Summary

23 day old baby admitted with seizures, intracranial calcifications, and ventriculomegaly who was diagnosed with congenital toxoplasmosis

Key Points

Some key references for the information below and reference when you have future cases!

A quick microbiology refresher on Toxoplasma gondii (T.gondii)

  • T.gondii is a protozoan and obligate intracellular parasite
  • You can find the life cycle on the CDC website and reproduced to the right
    • Unique biphasic life cycle (sexual cycle that occurs in felines + asexual cycle that can occur in other animals and humans)
  • Infectious forms: tachyzoites, tissue cysts containing bradyzoites, and oocysts containing sporozoites
  • The tachyzoite and corresponding host immune reaction are responsible for observed symptoms

T.gondii epidemiology

What are the clinical manifestations of congenital toxoplasmosis?

Toxoplasmosis in pregnancy

  • Mothers are not screened routinely for toxoplasmosis during pregnancy in the US
      • To be effective, screening would need to be done frequently to detect and in turn treat asymptomatic maternal infection (ideally within 3 weeks) >> but frequent rescreenign is costly and bothersome for patients
  • Incidence of acute primary T.gondii infection during pregnancy in US is estimated to be 0.2-1.1/1000 women on basis of data from MA and NH, which are the only 2 states in the US with universal newborn toxo screening
  • Congenital transmission occurs in most cases as a result of acute primary maternal infection acquired during pregnancy or within 3 months prior to conception
      • In utero infection rarely can occur as a result of reactivated disease in latently infected immunocompromised woman in absence of prophylaxis
      • Rarely, congenital toxoplasmosis is acquired from immunocompetent pregnant woman reinfected with different T.gondii strain
  • Critical illness is more likely to be severe in newborn when infection occurs in first trimester and is not treated during gestation
      • As gestational age increases, the risk of infection in fetus increases, but severity of disease decreases (those infected in 2nd and 3rd trimesters typically have mild or subclinical disease at birth)

What is involved in the initial evaluation of the newborn with suspected congenital toxoplasmosis?

  • Review maternal history and serology if available
  • Comprehensive physical exam 
      • See the clinical manifestations section above for more
      • The exam is going to be normal in most cases, but make sure to look for fever, jaundice, hepatosplenomegaly, neurologic changes, and other symptoms
  • Ophthalmology exam to look for chorioretinitis or other changes
  • Newborn hearing screening
  • LP for CSF: cell count and diff, glucose, protein, T.gondii PCR
      • CSF may demonstrate: elevated protein, hypoglycorrhachia, eosinophilia
  • In addition to CSF, various other samples can be sent for T.gondii PCR (at reference lab): urine, whole blood, vitreous fluid, BAL, cord blood, placenta
  • Neuroimaging which may demonstrate cerebral calcification
      • Head US: doesn’t capture calcifications as wel but often used in regions where symptomatic congenital toxo is low
      • Head CT: most sensitive for calcifications and can reveal brain abnormalities (like ventriculomegaly and hydrocephalus) when ultrasound studies are normally
          • Generally preferred
      • Brain MRI (but requires sedation)
  • Serology (paired baby and maternal serology testing) – more detail in the next section
      • Toxoplasma IgG
      • Toxoplasma IgM (ELISA or ISAGA)
      • Toxoplasma IgA (ELISA or ISAGA)
  • Other testing and screening
      • CBC with differential
      • AST, ALT, total and direct bilirubin
      • UA and Cr
      • G6PD deficiency evaluation
      • Evaluation for other infections on the differential (many congenital infections have clinical overlap!)
  • Abdominal US can be considered to evaluate for hepatosplenomegaly or intrahepatic calcifications

Let's focus on the Toxoplasma serology testing in more detail

  • So initial serology testing includes blood for IgG, IgM, IgA >> an accurate serologic diagnosis requires testing of blood from both infant and mother
      • Send as soon as possible after birth (however repeat testing may be necessary to exclude false positives)
  • Toxoplasma IgG
      • Doesn’t tell us the difference between maternal and infant infection in the newborn period
  • Toxoplasma-specific IgM
      • Indicates congenital infection if not contaminated with maternal blood
  • Toxoplasma-specific IgA
      • IgA is not always necessary but often useful and performed in conjunction with IgM at some reference labs 
      • Especially useful if IgG and IgM assays are indeterminate
  • Confirmatory testing for pregnant women with suspected acute Toxo infection or neonates with suspected congenital toxo should be sent to a reference lab, which are more sensitive than commercial labs.  Reference labs perform the:
  • A summary of neonatal diagnostic test results at birth or postnatally:
      • Confirmed diagnosis:
          • +IgG with +IgM (after DOL5) and/or +IgA (after DOL10)
          • +CSF T.gondii PCR
          • ↑IgG titer during 1st yr of life or ↑titer compared to mom
          • +IgG beyond 12 mo of age
      • Presumed diagnosis:
          • Characteristic clinical findings, +IgG, but negative IgM and IgA
      • Excluded:
          • -IgG, -IgM, -IgA
          • -IgM, -IgA with positive IgG titer that declines over time in absence of tx
  • A summary of some of the challenges of newborn serologic testing 
      • Toxoplasma IgG in newborn may reflect past or current infection in mother (IgG crosses placenta)
      • Fetal/newborn Ab response to T.gondii is variable. Depending on timing of maternal infection, Toxo-specific IgM may disappear before birth, may be demonstrated within first few days or life, or may be delayed in months
      • Antenatal treatment may affect the serologic profile of infant. IgM usually is undetectable or reduced, along with reduction in IgA, in infants exposed to anti-Toxo therapy with pyrimethamine and sulfadiazine in utero
      • Though maternal IgM and IgA Abs do not cross the placenta, small amounts can leak from the placenta which may results in low positive IgM or IgA in an uninfected infant shortly after birth
  • Repeat testing might be needed in certain scenarios:
      • Asymptomatic newborn infant; low suspicion for congenital toxo; initially IgG+, but IgM- and IgA- 
          • Follow-up IgG at 4-6 wk intervals until complete disappearance of IgG antibodies (usually within 6-12 months)
          • In absence of postnatal treatment, disappearance of IgG in the infant excludes a diagnosis of congenital toxo >> transplacentally derived maternal Toxo IgG is expected to decrease by 50% per month and usually becomes undetectable by 6-12 months of life
      • Asymptomatic newborn infant; positive initial IgM and/or IgA
          • Repeat testing at least 10 days after birth to determine if false positive
          • False positive IgM and IgA titers can occur following blood product transfusion >> repeat testing after at least 7 days after last transfusion
      • Negative initial results; strong clinical suspicion
          • May be false negative due to delayed antibody production or antenatal treatment
          • Retest 2-4 weeks after birth and every 4 weeks until 3 months of age
  • A few more resources in addition to those at top of the blog post:



Treatment of congenital toxoplasmosis

Most cases of acquired acute T.gondii infections in immunocompetent hosts do not require therapy but they DO if infection occurs during pregnancy, there is ocular involvement, or there are severe or persistent symptoms!!

Monitoring

  • While on medication, close safety/toxicity lab monitoring:
      • Monitor weekly for neutropenia (but can space out later if CBCs are stable)
          • If ANC decreases <750, frequency of folinic acid administration should be increased (to daily dosing) and pyrimethamine therapy should be temporarily held
  • Serology monitoring every 3-6 months until 18 months of age or completion of therapy (especially important for unconfirmed but highly suspected cases)
  • Ophthalmologic evaluations should be continued at least every 3-6 months during first 3 years of life (even if initial evaluation was normal)
      • Remember to discuss the chances of ocular re-activation later in life such as in puberty and the possible need for re-treatment
  • Hearing evaluation
  • Long-term neurologic/neurodevelopmental follow-up

Prevention

  • Pregnant women and immunocompromised patients whose serostatus for Toxo infection is negative or unknown should be counseled on how to avoid activities that may expose them to infection:
      • Decrease exposure to cat feces
          • Avoid changing litter boxes, gardening, landscaping
          • If these activities must be done:
              • Wear gloves and wash hands immediately after
              • Change cat litter daily to decrease risk of infection (oocysts are not infective during the first 1-2 days after passage)
          • Domestic cats can be protected from infection by feeding them commercially prepared cat food and preventing them from eating undercooked meat and hunting wild rodents and birds
      • Oral ingestion can be prevented by:
          • Avoiding consumption of raw or undercooked meat; smoked meat and meat cured in brine; raw shellfish; raw/unpasteurized milk; untreated water
          • Freezing meat to -20C for 48h before consumption
          • Washing fruits and vegetables

CCC Series Art & Infographics

Find all the Febrile infographics here!

Goal

Listeners will be able to understand the diagnosis and management of congenital toxoplasmosis

Learning Objectives

After listening to this episode, listeners will be able to:

  • Describe common features of congenital toxoplasmosis in a newborn
  • Describe the recommended diagnostic evaluation for suspected congenital toxoplasmosis
  • List the recommended treatment regimen as well as subsequent monitoring for children with congenital toxoplasmosis

Disclosures

Our guest (Jason Brophy) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Brophy, J., Dzora, E., Dong, S. “#39: Curious Congenital Conundrums – Seal of Approval ”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/77847ca3-b214-43de-8524-db41081f4b3b

Transcript

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