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Episode #37 – Curious Congenital Conundrums – Stop, Look, and Listen

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Summary

Drs. Nuria Sanchez-Clemente and Hermione Lyall discuss a case of congenital CMV in the first case of the Febrile “Curious Congenital Conundrums” series

Table of Contents

Credits

Hosts: Nuria Sanchez-Clemente, Sara Dong

Guest: Hermione Lyall

Writing: Justin Penner

Producing/Editing/Cover Art/Infographics: Sara Dong

Our Guests

Guest Consultant

Dr. Hermione Lyall

I am a consultant in paediatric infectious diseases at Imperial College Healthcare NHS Trust and Professor of Practice at Imperial College. I run both HIV and Congenital infection clinics at St Mary’s Hospital in London, and I am ward-attending consultant for Paediatric Infectious Diseases 4 months per year. I am a member of PENTA-ID and participate in HIV treatment trials for children. I have been actively involved in development of international courses for education for Paediatric Infections for many years, working with PENTA and the European Society for paediatric Infectious Diseases (ESPID). From 2018 – 2021, I was a member of the board of ESPID. I am now a Trustee on the board of the ESPID Foundation.  In 2020, with colleagues from around Europe, we set up CCMVNET (ccmvnet@gmail.com ) – an international network built around a registry of children with congenital CMV, currently I am chair of the network. Our aim is to learn as much as possible about this condition, and promote collaboration for research into prevention and treatment.  Fundamentally, I am  a front line clinician who can bring people together – children, families and peer supporters ,clinicians, laboratory scientists, epidemiologists, virologists, pharmacologists, and trialists,– all the team that we will need to change the future for children with congenital infections.

Guest Co-Host

Dr. Nuria Sanchez-Clemente

I am a paediatric registrar and NIHR (National Institute for Health Research) Academic Clinical Lecturer in paediatric infection and immunity at St. George’s University, London. My academic and clinical interests are around congenital infections, arboviruses, neglected tropical diseases and migrant health. In 2010 I undertook an MSc in Tropical Medicine at The London School of Hygiene (LSHTM) and Tropical Medicine and travelled to Peruvian Andes to undertake the first systematic review on Peruvian Bartonellosis. From 2014-2017 I lived in Brazil where I did my PhD on congenital Zika syndrome, studying the perinatal outcomes of a Zika pregnancy cohort in the state of Sao Paulo. Since then, I have continued to work with teams in Brazil, LSHTM and WHO to study the long term consequences for children born with congenital Zika infection and the wider impacts on their families and societies. My more recent academic and clinical interests are around migrant health and health inequalities and I am studying large primary care datasets in order to compare patterns of paediatric primary and secondary healthcare usage between migrants and non-migrants in the UK. In the last year I have also been working on the ‘Respond’ Refugee Family Project at UCLH, leading infectious diseases clinics for Unaccompanied Asylum Seeking Children and have been working as a volunteer with Doctors of the World studying maternal and postnatal outcomes. Ultimately, I hope through my research and clinical endeavours to work towards improving the health of the most marginalised communities.  

Culture

Hermione shared Anthony Doerr’s book Cloud Cuckoo Land, “if you want an amazing book that has everything about humanity in it, the past, the present, the future”

Consult Notes

Case Summary

  • 29 year old G2P1 previously healthy woman at 14 weeks gestation who developed a rash, fever, cough, pharyngitis who was found to be CMV IgM+/IgG-, low avidity, +urine CMV PCR
  • Baby was born at 38 weeks gestation and found to have positive urine and saliva PCR with MRI that demonstrates polymicrogyria.  She was diagnosed with congenital CMV and treated with valganciclovir

Key Points

Congenital CMV infection has a wide range of clinical manifestations

  • Let’s define some terminology that is frequently used first.  Infants with congenital CMV infection are classified according to whether they have symptoms at the time of birth:
      • Symptomatic (one or more symptoms at birth)
      • Primary neurophenotype (refers to patients with only CNS manifestations; newly described category, some inconsistency in published literature)
      • Asymptomatic (no apparent symptoms at birth; important to note that these infants may still develop hearing loss or symptoms later in life)
      • Asymptomatic with isolated hearing loss (this categorization is a bit inconsistent as well, as Hermione noted in the episode)
  • ~10% of infants with congenital CMV infection will exhibit findings at birth (symptomatic disease).  These findings may include:
      • Jaundice, direct hyperbilirubinemia
      • Petechiae/purpura due to thrombocytopenia
      • Hepatosplenomegaly
      • Small for gestational age
      • Microcephaly
      • Intracerebral (typically periventricular) calcifications
      • Chorioretinitis
      • Sensorineural hearing loss (more on this next)
      • Hemolytic anemia
      • Lethargy, hypotonia
      • Seizures
      • ~10% of symptomatic congenital CMV infected babies will have severe life-threatening disease such as sepsis like illness, myocarditis, viral induced hemophagocytic lymphohistiocytosis and/or other severe end organ involvement
      • Developmental delays can occur among affected infants in later infancy and early childhood
      • Death attributed to congenital CMV occurs in 3-10% of infants with symptomatic disease

Congenital CMV is the leading non-genetic cause of sensorineural hearing loss in children in the US

We will focus on congenital infection in these Consult Notes, but remember that CMV transmission can occur horizontally (by direct person-to-person contact with virus-containing secretions), vertically (from mother to infant before, during, or after birth), via transfusions from infected donors, and solid organ or hematopoietic stem cell transplantation.  A few summary points on horizontal and vertical transmission with this episode:

The diagnosis of congenital CMV relies on a high index of suspicion, such as what we had in this case.  Here is a quick summary of clinical scenarios to think about congenital CMV infection:

  • Newborn with signs, symptoms, or abnormal neuroimaging consistent with congenital CMV disease (as noted previously)
  • Newborn with documented sensorineural hearing loss regardless of whether it is accompanied by other CMV symptoms
  • Newborn born to mother with known or suspected CMV infection during pregnancy, including:
      • Maternal seroconversion during pregnancy
      • Presumed maternal primary CMV infection (based on IgG/IgM)
      • Mononucleosis like illness during pregnancy
      • Abnormal fetal imaging
  • Immunocompromised babies

So how do we go about testing/diagnosis?  Hermione outlined her approach of (1) confirming if this is congenital CMV with diagnostic testing (2) then detecting whether there are end-organ sequelae of congenital CMV

Congenital infection requires detection of CMV or CMV DNA in urine, saliva, blood, or CSF obtained within 3 weeks of birth (detection beyond this initial period of life could reflect postnatal acquisition of virus)

 

 

Next, the evaluation would look for detection of possible sequelae of congenital CMV.  This generally includes: ophthalmology exam, heading imaging, CBC, LFTs

  • For neuroimaging, brain MRI and head ultrasound are used:
      • Ultrasound should be obtained in all infected babies.  US is good for detecting calcifications and is better able to detect lenticulostriate vasculopathy than advanced imaging >> it will detect most major, obvious abnormalities
      • Most infants with abnormal US, abnormal neuro exam, seizures, or other concerns will undergo more advanced neuroimaging:
          • MRI can show classic signs such as periventricular cysts, increased white matter intensity.  MRI is more sensitive in detecting vasculitis, polymicrogyria (and other neuronal migration disorders, which are associated with early infection and most serious consequences).  Hermione pointed out that dilated ventricles can be seen, but this is often more representative of the loss of brain tissue
          • CT may be considered, but requires radiation exposure.  MRI is more sensitive but often may be limited by longer procedure time, need for sedation

Just to back-up a little bit, I wanted to summarize a few of the points related to CMV infection in pregnancy

Is there anything we can do to prevent transmission to baby?  In this episode’s case, the example patient declined any intervention, but the possibility of providing therapy to mother during pregnancy to prevent infection was discussed

  • First off: There is another section on screening of neonates later, but what about during pregnancy?  Will note here that there is no consensus on whether all women of childbearing age should know their CMV serostatus.  Some experts suggest that women should be screened while other professional organizations (such as American College of Obstetricians and Gynecologists; Society for Maternal-Fetal Medicine) recommend against routine screening
  • Recommend against routine serologic screening for CMV
        • No vaccine available for seronegative women
        • In seropositive women, difficult to distinguish between primary and nonprimary infection as well as the timing of infection
        • Seropositive women remain at risk from reactivation of latent virus and/or reinfection with new viral strain
        • No clear evidence that antiviral treatment or hyperimmune globulin prevents infection or sequelae
        • If fetal infection is detected, no clear way to predict whether fetus will develop sequelae
        • Routine screening could lead to unnecessary and/or harmful intervention
  • Proponents of universal screening
        • Knowledge of seronegative status and counseling may increase some patients’ motivation to practice good hygiene and thus decrease risk of seroconversion during pregnancy

So what are the interventions that have been studied?

 

 

Which infected infants with congenital CMV should be treated?

How to treat:

  • Antiviral therapy should be started once testing is confirmed, and benefit has been shown by starting within first 30 days of life
  • Oral valganciclovir or IV ganciclovir is used (depends on severity of disease and whether infant has any conditions that would impact absorption of enteral meds)
  • Notes on medication monitoring:
      • Needs about monthly dose adjustments to account for weight gain
      • Significant neutropenia occurs in ~20% of infants treated with oral valganciclovir and in ~66% of infants treated with parenteral ganciclovir.  Neutropenia (when occurs) is more common during first 4-6 weeks of therapy
      • More uncommonly, thrombocytopenia can occur
      • Hepatotoxicity and nephrotoxicity are observed in some infants

What monitoring do these children need?  

  • Serial audiologic and ophthalmologic assessments
  • CNS manifestations such as intellectual disability, cerebral palsy, and seizures may require special services such as speech, language, occupational, and/or physical therapy
  • These babies also can develop behavioral disorders, such as autism spectrum disorder

A few quick notes on newborn screening for congenital CMV.

 

A few final notes from Hermione:

  • She mentioned CMV Action, which is a resource in the UK from families of children with congenital CMV.  They provide information for healthcare workers and the public as well as a source of peer support.  Check your local area to see if there are peer supports for your patient and their family
  • She mentioned the importance of collaboration and research, such as CCMVNET which is a European clinical network including a registry of children affected by congenital CMV
  • There are still so many questions we don’t understand!
      • Why are some babies more severely affected than others?  That develop hearing loss or do not?
      • Why can you have hearing loss at birth as well as a toddler?
      • Is it virological? Immunological? A combination?

CCC Series Art & Infographics

Find all the Febrile infographics here!

Goal

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

Learning Objectives

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

  • Define symptomatic congenital CMV infection and the features of CMV disease in a newborn
  • Interpret available diagnostic testing for congenital CMV infection
  • Describe the recommended treatment for congenital CMV infection in a symptomatic neonate

Disclosures

Our guest (Hermione Lyall) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Lyall, H., Sanchez-Clemente, N., Dong, S. “#37: Curious Congenital Conundrums – Stop, Look, and Listen”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/edbac33a-6604-44de-8071-9b0050b42e38

Transcript

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