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Episode #41 – Curious Congenital Conundrums – In the Eye of the Beholder

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Summary

Drs. Carsten Kruger, Clare Nourse, and Justin Penner discuss how they approach a case of congenital syphilis in the third case of the Febrile “Curious Congenital Conundrums” series.

Table of Contents

Credits

Host(s): Carsten Kruger, Sara Dong

Guest: Clare Nourse, Justin Penner

Writing: Justin Penner

Producing/Editing/Cover Art/Infographics: Sara Dong

Our Guests

Guest Consultant

Dr. Clare Nourse

Professor Clare Nourse is a Paediatric Infection Specialist at Queensland Children’s Hospital in Brisbane and Professor in the School of Clinical Medicine at the University of Queensland. She qualified in medicine from Trinity College Dublin and

trained in Dublin, Melbourne and Brisbane. Her particular interests are in HIV, TB and syphilis infection in children, tropical

infection and infection in resource limited countries, particularly in Timor-Leste.  She travels regularly to Timor Leste and is a founder and board director of Maluk Timor, a not for profit organisation in Dili, for which she chairs the

Medical Advisory Committee. Her particular research interests are in the translation of epidemiology of infection in children to clinical practice

Guest Consultant

Dr. Justin Penner

Justin completed his medical school and paediatric residency at the University of Manitoba in Winnipeg, Canada. Always having an interest in infectious disease, he subsequently completed an MSc in Tropical Medicine and International Health at the London School of Hygiene and Tropical Medicine followed by a fellowship in paediatric infectious diseases at St Mary’s Hospital in London, UK and a fellowship in paediatric immunocompromised ID at Great Ormond Street Hospital. Justin is a member of the PENTA network educational group on congenital infections and has a particular interest in indigenous health in the Canadian North. He currently works as a paediatric infectious diseases consultant at the Children’s Hospital of Eastern Ontario in Ottawa, Canada and at the Qikiqtani General Hospital in Iqaluit, Nunavut and as an honourary academic fellow at Great Ormond Street Hospital.

Guest Co-Host

Dr. Carsten Krueger

Carsten Krueger attended medical school at the University of Calgary, before completing a residency in pediatrics at the University of Toronto. Currently he is completing a fellowship in pediatric infectious diseases at the University of Ottawa, and is co-principal investigator of the national Canadian Pediatric Surveillance Program study on Congenital Syphilis.

Culture

Justin and Clare shared their love of tennis, both playing and watching

Carsten shared his recent kitchen creation of Quebecois brie with cranberry maple pecan cheese

Consult Notes

Case Summary

31 yo woman with new diagnosis of uveitis was found to have diagnosis of syphilis.  Her newborn baby had developed pancytopenia, lymphadenopathy, and hepatosplenomegaly, and they were ultimately diagnosed with congenital syphilis.

Key Points

Let's start with some resources!

  • AAP Red Book 2021-2024 Report: Syphilis Chapter
  • CDC STI Guidelines, 2021, Syphilis section here
  • BASHH Syphilis Guidelines here as well as the UK National Guidelines on Syphilis 2015 here
  • Queensland Clinical Guidelines for Syphilis in pregnancy are here

A quick reminder about the etiology and microbiology of syphilis!

  • Bacterial infection caused by T.pallidum subspecies pallidum 
    • Thin, motile spirochete
    • Extremely fastidious
    • Humans are the only natural host
  • Other closely related organisms causing human disease in distinct geographic regions of the world:
    • T.pallidum subspp pertenue = yaws
    • T.pallidum subspp endemicum = endemic syphilis
    • T.carateum = pinta

Our guest discussants touched on the evolving epidemiology of syphilis during the episode, which has demonstrated dramatic increases in congenital syphilis cases in various areas.

 

  • Cases of reported congenital syphilis in the US has increased dramatically since 2012.  This incidence of congenital syphilis reflects the rising rate of syphilis in women of childbearing age
  • During 2019, a total of 1870 cases were reported, including 94 stillbirths and 34 infant deaths
    • The national rate of 48.5 cases/100,000 live births is a 41% increase compared to 2018 and 477% increase relative to 2012
    • You can find more about syphilis surveillance in US on this page
  • From Clare’s perspective in Australia, she noted the increasing rates in areas of northern and central Australia
    • Here’s some information on the syphilis outbreak affecting Aboriginal and Torres Strait Islander people living in Australia from the Australian Government Department of Health
  • Here is a report on congenital syphilis in England 2015-2020 reported to NHS
  • As mentioned by our guests, identifying women at increased risk of syphilis can be challenging

Transmission of T.pallidum in congenital syphilis

  • Congenital syphilis can be contracted at any stage of maternal infection via:
      • Transplacental transmission at any time during pregnancy (through transmission of spirochetes in maternal bloodstream)
      • Contact with maternal lesions at time of delivery
  • T.pallidum is not transmitted through human milk, although transmission may occur if breastfeeding mother has infectious lesion (chancre) on breast)
  • Transplacental transmission can occur at any time during gestation, but the risk of transmission increases directly with gestational age 
  • Women with untreated primary or secondary syphilis are more likely to transmit syphilis than women with latent disease (60-90% vs. 40% in early latent vs. <10% in late latent syphilis)
  • Among pregnant women with untreated early syphilis, up to 40% of their pregnancies will result in spontaneous abortion, stillbirth, or perinatal death

What are the typical clinical manifestations of congenital syphilis?

Congenital syphilis is often defined as either:

  • Early congenital syphilis (onset within 2 years of birth), or
  • Late congenital syphilis (onset of manifestations after 2 years of age)

Early congenital syphilis

  • Symptoms in untreated infants usually appear by 3 months of age, most often by 5 weeks
  • ~60-90% of newborns with congenital syphilis are asymptomatic at birth
  • Intrauterine infection can result in stillbirth, hydrops fetalis, or preterm birth
      • Placenta may be large, thick, and pale
      • Umbilical cord may have inflammation with abscess like foci of necrosis within Wharton’s jelly (necrotizing funisitis)
  • Symptomatic infants may have:
      • Hepatosplenomegaly
      • Jaundice (due to syphilitic hepatitis and/or hemolysis)
      • Nasal discharge (“snuffles”, copious nasal secretions, often after first week of life – *note* contains spirochetes and is infectious!!)
      • Generalized lymphadenopathy
      • Rash (maculopapular consisting of small dark red-copper spots that are most severe on hands and feet – *note* contains spirochetes and is infectious!! ) and/or mucocutaneous lesions
          • Rash may associated with desquamation or scaling, particularly on palms or soles
          • Usually maculopapular rash will appears 1-2 weeks after rhinitis
          • Some children may have a vesicular rash (pemphigus syphiliticus) or condylomata lata as well (*note – these are also infectious!)
      • Musculoskeletal abnormalities (such as osteochondritis, periostitis, pseudoparalysis)
      • Failure to thrive
      • Other possibilities include: pneumonia, edema, hemolytic anemia, thrombocytopenia, CSF abnormalities, nephrotic syndrome

Late congenital syphilis

  • Untreated infants, including those asymptomatic at birth, may develop late manifestations (usually after 2 years of age) – these manifestations are related to inflammation from early infection 
  • Some manifestations of late congenital syphilis can be prevented with treatment, however others (such as keratitis) may occur despite appropriate therapy
  • Manifestations may include:
      • Interstitial keratitis (bilateral, often near puberty age), corneal scarring
      • CN8 sensorineural hearing loss (usually near age 8-10 yo)
      • Frontal bossing
      • Saddle nose
      • Short maxilla, protuberant mandible
      • Hutchinson teeth (peg-shaped, notched central incisors), mulberry molars (maldevelopment of cusps of first molars), perforation of hard palate
      • Rhagades (perioral fissures radiating from mouth)
      • Skeletal changes:
          • Anterior bowing of shins (saber shins)
          • Enlargement of sternoclavicular portion of clavicle (Higoumenakis sign)
          • Painless arthritis of knees (Clutton joints)
      • Gummas in skin or mucous membranes
      • Intellectual disability, CN palsies
  • You likely learned the Hutchinson triad: Hutchinson teeth, interstitial keratitis, sensorineural hearing loss
      • This triad, mulberry molars, and Clutton joints are relatively specific for congenital syphilis

Diagnostics for congenital syphilis

  • Definitive diagnosis is made when spirochetes are identified by microscopic darkfield exam of lesion exudate, nasal discharge, or tissue but,
      • Specimens from mouth lesions can contain nonpathogenic treponemes that can be difficult to distinguish from T.pallidum by darkfield
      • Darkfield microscopy is not routinely available in many labs due to availability and complexity
  • T.pallidum can be detected by PCR assay as well, but these are often not widely available

So we typically are using serologic testing to establish a diagnosis of proven/highly probable, at-risk, or unlikely congenital syphilis infection.  Serologic tests include nontreponemal tests and treponemal tests, read more about them below in the setting of congenital syphilis.  You can also check out a prior syphilis episode of Febrile for more on syphilis serologies as well.

  • Nontreponemal tests = VDRL, RPR
      • Inexpensive
      • Can be performed across range of lab levels of complexity
      • Relatively rapid turnaround times
      • Semiquantitative results that can help define disease activity and monitor response to therapy
      • False negatives can occur in setting of: 
          • Early primary syphilis
          • Latent acquired syphilis of long duration
          • Late congenital syphilis
          • Prozone phenomenon (high concentrations of antibody will be weakly reactive or falsely negative; can dilute serum to result in positive test; most often with HIV coinfection)
      • *In the neonatal infection setting, nontreponemal tests are useful because quantitative results can be compared simultaneously with maternal results*
          • Neonate’s nontreponemal titer is usually 1-2 dilutions less than mother
          • If mother’s titer is low, the neonate may have nonreactive serology, but still would be at risk for congenital syphilis
      • Outside of congenital infection, a reactive nontreponemal test result should be confirmed by specific treponemal tests to exclude false positive.  More on false positives like that in the other syphilis episode
  • Serologic IgG tests are problematic in setting of newborn because it is not possible to differentiate passively acquired maternal antibody and endogenous Ab produced by baby
      • There is not a sensitive/specific IgM assay available for routine use to assess for congenital syphilis
  • A few quick notes on CSF abnormalities that may be seen:
      • Increased CSF protein
      • Increased CSF WBC count (can be difficult to interpret as normal values differ by gestational age and are higher in preterm infants)
      • Reactive CSF VDRL
          • Outside of neonatal period, CSF-VDRL is highly specific but insensitive (so negative result doesn’t exclude neurosyphilis)
          • Reactive CSF-VDRL in neonate can be result of nontreponemal IgG antibodies that cross the blood-brain barrier

So how do we approach diagnosis of congenital syphilis?!

  • This is difficult and often is a delayed or missed diagnosis
  • You can find algorithm for evaluation and management of syphilis in the resources at the top of the Consult Notes
  • The CDC and AAP guidelines recommend maternal samples be screened according to traditional algorithm (nontreponemal test followed by treponemal test if positive), although some labs will screen in the reverse
  • The diagnosis of congenital syphilis should be suspected in all infants born to women with reactive syphilis testing or in those with nonspecific clinical findings consistent with congenital syphilis (noted above)
  • We’ll look at initial evaluations below:

Testing during pregnancy

  • False negative results are possible in recent infection, and syphilis may be acquired later in pregnancy
  • In those at risk or with suspicion for infection, serologic testing should be performed at 28 wks gestation and again at delivery
  • As noted above, the CDC and AAP recommend screening based on traditional algorithm (nontreponemal then treponemal testing)
      • Retesting in 2-4 wks and again later might be necessary if clinically indicated (should be considered for pregnant woman at risk)
  • If reverse sequence screening algorithm used, pregnant women with reactive treponemal screen should have confirmatory testing with nontreponemal testing >> if nontreponemal test is negative, second trep-specific test should be used
  • US evaluation of fetus from 2nd trimester onward should be performed when syphilis diagnosed at any time during pregnancy
  • Pathologic exam of placenta and/or umbilical cord should be obtained

Evaluation of infants for congenital syphilis under the age of one month

  • All infants born to seropositive mothers require careful physical exam and nontreponemal testing
      • Neg maternal RPR or VDRL result at delivery doesn’t rule out possibility of infant having congenital syphilis, although this is rare
  • Ideally there would be pathologic examination of placenta or umbilical cord if possible
  • Some key information to gather:
      • Mother’s risk factors for syphilis
      • Mother’s serology results
      • If mother was treated: timing of treatment (before or after pregnancy; more than 4 weeks before delivery?), adequacy of treatment
  • See Fig 3.15 in the AAP Red Book 

Evaluation of infants >1 mo of age and children

  • Infants and children identified as having reactive serologic tests for syphilis should have maternal serologic test results and records reviewed to assess whether they have congenital or acquired syphilis – this distinction might be difficult though (the key information noted above about maternal history is important here as well)
  • Additional evaluation may include (from AAP Red Book):
      • CSF analysis for VDRL, cell count, protein
      • CBC with differential
      • Other tests as indicated: long-bone radiographs, chest x-ray, LFTs, AUS, ophtho, neuroimaging, auditory brain-stem response
      • Evaluation and testing for HIV
      • May need to consider echo if cardiac concerns

The categories of congenital syphilis are described below.  

  • Proven or highly probable congenital syphilis: if neonate <1 mo of age has any of these below
      • Abnormal clinical findings consistent with congenital syphilis
      • Serum quantitative nontreponemal titer ≥4-fold corresponding maternal titer (this is equivalent to two dilutions)
      • Positive darkfield or fluorescent Ab test of lesions, body fluid, placenta, umbilical cord
      • These babies should have additional evaluations noted above
  • Possible congenital syphilis:
      • Normal physical exam
      • Serum VDRL or RPR titers <4-fold corresponding maternal titer
      • Mother was not treated or received inadequate/suboptimal therapy
      • Some experts might also include infants whose mother had contact with person with primary or secondary syphilis within 90d prior to delivery and were not treated (even if mother has nonreactive serology)
  • Congenital syphilis less likely:
      • Normal physical exam
      • Serum VDRL or RPR titers <4-fold corresponding maternal titer
      • Mother received appropriate treatment >4 wks before delivery
      • Mother has no evidence of reinfection or relapse
  • Congenital syphilis unlikely:
      • Normal physical exam
      • Serum VDRL or RPR titers <4-fold corresponding maternal titer
      • Mother received appropriate treatment >4 wks before delivery
      • Mother has no evidence of reinfection or relapse
      • Mother’s titer remains low (RPR<1:4), stable before and after pregnancy
  • Congenital neurosyphilis:
      • LP should be performed in:
          • Infants <1 mo with proven or highly probable congenital syphilis
          • Infants <1 mo whose mothers were not adequately treated (possible syphilis)
          • Infants and children with reactive serologic tests for syphilis at ≥1 mo of age

So how do we treat?

You’ll see information on treatment based on the AAP Red Book recommendations below for infants up to one month of age (Table 3.66).

Preferred

Aqueous crystalline penicillin G, 50 000 U/kg IV every 12 hrs (1 wk of younger), then every 8 h for infants older than 1 wk

10 days total

Or

Procaine penicillin G, 50 000 U/kg IM as single daily dose

10 days total

Preferred

Aqueous crystalline penicillin G, 50 000 U/kg IV every 12 hrs (1 wk of younger), then every 8 h for infants older than 1 wk

10 days total

Or

Procaine penicillin G, 50 000 U/kg IM as single daily dose

10 days total

Or

Benzathine penicillin G, 50 000 U/kg IM 

Single dose (recommended by some experts, but only if all components of evaluation are obtained and normal and follow-up is certain).  Many experts would still prefer the 10 day course though

Preferred

Benzathine penicillin G, 50 000 U/kg IM 

Single dose

Alternatively, infants whose mothers’ nontreponemal titers decreased at least fourfold after appropriate therapy for early syphilis or remained stable at low titer (RPR ≤1:4) may be followed every 2-3 mo without treatment until nontreponemal test becomes nonreactive

Nontreponemal antibody titers should decrease by 3 mo of age and should be nonreactive by 6 mo of age; patients with increasing titers or with persistent stable titers 6-12 mo after initial treatment should be reevaluated, including a CSF examination, and treated with penicillin G IV x 10 day course (even if treated previously)

None, but infants with reactive nontreponemal tests should be followed to ensure test result returns negative

Benzathine penicillin G, 50 000 U/kg IM single dose can be considered if follow-up is uncreatin and infant has reactive test (some experts)

Neonates with negative nontreponemal test result at birth and whose mothers were seroreactive at delivery should be retested at 3 mo to rule out incubating congenital syphilis

  • Management of congenital syphilis in infants >1 month of age
      • Infants >1 mo of age (including those with late congenital syphilis) and children with acquired syphilis should receive:
          • Aqueous penicillin G 50 000 U/kg IV every 4-6 hrs x 10 days
      • Some experts suggest giving such patients a single dose of PCN G benzathine (50k U/kg IM, not to exceed 2.4million U) after 10d course of IV aqueous crystalline PCN
      • If patient has no clinical manifestations of disease, CSF exam normal, CSF-VDRL neg >> some experts would treat with 3 weekly doses of PCN G benzathine (50k U/kg IM not to exceed 2.4million U)
  • Some special notes related to treatment:
    • If more than 1 day of therapy missed, entire course should be restarted
    • Data to support use of other agents for treatment of congenital syphilis are not available
        • It is recommended to desensitize and still treat with penicillin if patient has allergy
    • When possible, full 10d course of penicillin is preferred, even if ampicillin initially used to possible sepsis

Monitoring and follow-up: All infants with reactive serologic tests for syphilis or were born to mothers who were seroreactive at delivery should receive careful follow-up during well child visits

  • Serologic nontrep tests should be performed every 2-3 mo until test is nonreactive
  • Treatment failure would be indicated by:
      • Failure of VDRL or RPR titers to decline
      • Increasing or persistent VDRL or RPR titers after 6-12 mo of age (or treatment in children treated after neonatal period)
  • In cases noted above concerning for treatment failure, the child should have re-evaluation including CSF exam
      • Retreatment with 10d course of IV PCN G indicated, even if treated previously
  • Neonates with neg nontreponemal test at birth who mothers was seroreactive at delivery should be retested at 3 mo to r/o incubating congenital syphilis
  • Treponemal tests should not be used to eval treatment response, because results may remain positive despite therapy
      • Passively transferred maternal trep Ab can persist in infant until 15 mo of age
      • Reactive trep test after 18 mo of age is diagnostic of congenital syphilis and should be followed by evaluation and if necessary treatment
  • Serial CSF evaluation may be used in infants with initial abnormal CSF evaluation, but there is a variety in practice patterns related to repeat LPs.  Some will evaluate CSF every 6 months until normal, but others are moving away from that towards more clinical progress.  Some may not repeat the LP unless the infant exhibits persistent nontreponemal test titers at age 6-12 mo
      • After 2 years of follow-up, reactive CSF VDRL test or abnormal CSF indices that cannot be attributed to another ongoing illness are indications for retreatment
  • Neonates should have appropriate yearly hearing, ophthalmologic, and neurodevelopmental monitoring

CCC Series Art & Infographics

Find all the Febrile infographics here!

Goal

Listeners will be able to approach the diagnosis and management of congenital syphilis

Learning Objectives

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

  • Describe common features of congenital syphilis in an infant
  • Describe the recommended diagnostic evaluation for suspected congenital syphilis
  • Identify the treatment regimen and monitoring recommended for children for likely congenital syphilis

Disclosures

Our guests (Clare Nourse and Justin Penner) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Krueger, C., Nourse, C., Penner, J., Dong, S. “#41: Curious Congenital Conundrums – In the Eye of the Beholder”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/b786c3a8-0297-479f-b0e0-f8c43bc1d628

Transcript

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