CCMV Public Health and Policy Conference Series: Standardized Case Definitions for Congenital CMV

CCMV Public Health and Policy Conference Series: Standardized Case Definitions for Congenital CMV

Author: Dr. Megan Pesch
In October of 2023, researchers, clinicians and families from around the world gathered in Salt Lake City, Utah for the Congenital CMV Public Health and Policy Conference. It was an exciting three-and-a-half days-- jam packed with presentations about the latest clinical practices and research findings, as well as congenital CMV families sharing their experiences and lessons learned from their own journeys. This series highlights some of the presenters and their work featured at the conference, to share with our NCMVF community. In this installment, we discuss the creation of standard case definitions for congenital CMV.  

Dr. Stephanie Browning McVicar is the Director of the Early Hearing Detection and Intervention (EHDI) Program and the lead of the Congenital Cytomegalovirus (CMV) Public Health Initiative in Utah, and has been since the program’s inception. Dr. McVicar played an instrumental role in the passing of the 2013 congenital CMV hearing-targeted screening and public health awareness legislation in Utah, the first of its kind in this country. Over the last decade Dr. McVicar and her team have worked tirelessly to implement and improve the process of cCMV screening and continue to keenly monitor data to ensure timely cCMV testing and follow up to provide cCMV-affected babies treatment and intervention.
Max Sidesinger, MPH, is the CMV data coordinator and an epidemiologist for Utah’s Early Hearing Detection and Intervention Program. He collects information on every CMV test completed on a child under 1 year of age in Utah, per the state Communicable Disease Rule, and works with providers and families to ensure CMV testing for children who fall under Utah's CMV Public Education and Testing Mandate. Max provides analyses for both CMV and EHDI related data.  Along with Dr. McVicar, he has collaborated with researchers at the University of Utah on multiple newborn hearing-related projects, with the CDC on a pilot surveillance project for cCMV, and with the CSTE on a position statement for standardized cCMV surveillance.
Mr. Max Sidesinger gave a presentation at the recent Congenital CMV Public Health and Policy Conference, entitled “Establishing standardized case definitions for congenital cytomegalovirus (cCMV) infection and disease in the United States”. He and the submitting and presenting author of the new case definition, Dr. Stephanie Browning McVicar, recently sat down with me to answer some questions and share highlights of their team’s case definition presentation.

1. Let’s start off with some basics. What are standardized case definitions in public health research and why are they important?  

It is very important in public health surveillance that jurisdictions are utilizing the same definitions for 1) reporting cases and 2) classifying cases.  If everyone isn’t using the same definitions, then comparisons across the US aren’t meaningful, i.e. to use a good old cliché, jurisdictions would be comparing apples to oranges instead of apples to apples. Standardized case definitions for congenital CMV (cCMV) were imperative because multiple US jurisdictions were conducting cCMV screening and surveillance but using various methods and inclusion criteria for case ascertainment, reporting, and classification.

2. In terms of congenital CMV, why did your team feel that it was important to work on a standardized case definition?  

Utah was the first state to mandate in law the testing of newborn infants for congenital CMV infection. Our law is “hearing-targeted”, meaning testing should be completed on infants failing newborn hearing screening/s. Since our law started in 2013, several other states have mandated CMV testing in newborns, and we have tested more than our mandate specifies by including any newborn with congenital CMV risk factors. There are also jurisdictions conducting CMV testing without a state mandate. As more and more entities are conducting CMV testing and public health surveillance, having a standardized case definition became urgent. This will allow for standardized inclusion criteria for case ascertainment, reporting, and classification. Having these standardized case definitions for both cCMV infection and disease will help us understand the epidemiology of cCMV and compare trends across the United States. They will also help us capture the true burden of cCMV disease.

3. It sounds like you assembled a big team to work on the creation of the standardized case definition for congenital CMV, can you tell us a bit about that process?  

Another cliché, but it really did take a village! There was a large number of experts from the Centers for Disease Control and Prevention (CDC), public health and medical epidemiologists, and several subject matter experts (SMEs) in clinical practice and research like infectious disease and pediatrics. Although there are 18 individuals listed as SMEs and authors on the position statement, there were more than 60 who contributed overall. We are grateful for each and every one of them!

As for the process itself, it took longer than a year and involved many, many meetings and discussions, position statement drafts and presentations.  Our position statement ultimately was voted on and passed unanimously at the CSTE annual conference in June 2023 – and as luck would have it, the conference was held right here in Salt Lake City!

4. Wow, thank you for doing all of that work! After you settled on the final case definitions, I understand that you had to submit them for approval by the Council of State and Territorial Epidemiologists. Can you tell us what this group is?  

First, because some people may not be familiar with epidemiology, I’d like to give a definition of epidemiologist from the Bureau of Labor Statistics. Epidemiologists are public health workers who investigate patterns and causes of disease and injury. They seek to reduce the risk and occurrence of negative health outcomes through research, community education and health policy.
CSTE, or the Council of State and Territorial Epidemiologists, is the national home of public health epidemiologists. The organization works hard to advance public health policy and epidemiologic capacity across the United States and their territories. CSTE provides technical advice and assistance to partner organizations and to federal public health agencies such as the CDC. They currently have committees in the following areas: Infectious Diseases; Chronic Disease, Maternal & Child Health; Environmental and Occupational Health; Surveillance & Informatics; Injury, Substance Use & Mental Health; Workforce Development; Health Equity and Tribal Epidemiology; Health Security, Policy, and Law.  Position statements are documents developed by CSTE members that are focused either on policy issues or case definitions for diseases and conditions. These documents reflect the consensus opinion of CSTE’s membership on each specific topic and are developed in close partnership with the CDC. Case definition position statements, known as standardized surveillance position statements, create disease case definitions that can be adopted by all health departments and the CDC for use in public health surveillance. This allows for cases of specific diseases to be defined the same way nationally.

5. Finally, can you share what the standardized case definitions for cCMV are?

A standardized surveillance case definition contains two main parts: 1) what disease or condition-related patient information should healthcare providers and other data reporters report to public health so that epidemiologists can investigate that condition and 2) what constitutes a confirmed, probable, or suspect case. 
The full eport, which is quite complex published on the CSTE website.

To summarize the highlights:

A case should be reported to public health for investigation if a CMV lab test is positive on an infant OR CMV is listed on a death certificate as a contributing factor in the infant’s death OR a child 6 years of age or younger has a diagnosis of cCMV infection in their healthcare record OR an infant aged 45 days or younger has a diagnosis of CMV disease in their healthcare record.

As cCMV testing is very time-sensitive, i.e., samples must be taken before the infant is 21 days old to distinguish between a congenital (before birth) vs. an acquired (after birth) infection, laboratory criteria are broken down into confirmatory vs presumptive based on when the samples were taken when the test is positive (<21 days for confirmatory; 22-42 days for presumptive). Since cCMV tests on saliva specimens have shown significant false positive rates in various studies due to breast milk contamination, positive results on saliva samples on their own only count as presumptive evidence, even if collected before 21 days of age.
To differentiate between a case of cCMV infection vs disease: infection means confirmatory laboratory evidence is present without clinical signs; disease means confirmatory laboratory evidence is present AND clinical criteria has been met.  We did add a probable disease case classification when clinical criteria are met along with presumptive laboratory evidence.

6. In your opinion, are these standardized case definitions supposed to be used only in epidemiology research about newborns with congenital CMV? Could these same definitions be used clinically, for instance instead of the classic “symptomatic” and “asymptomatic”? What about for older children?  

Our position statement lists that case ascertainment is the process through which public health identifies potential cases of a disease or condition using data reported or provided to public health by healthcare, laboratories, and other reporting entities. This public health reporting is triggered by the case ascertainment criteria including in this position statement, and each initial report sent to public health should include common data elements and disease-specific data elements. Case ascertainment criteria are not intended to be used for clinical diagnosis purposes.  That being said, historically there has been differing thoughts on the use of “symptomatic” vs “asymptomatic” nomenclature although they have been prominently used for years. The discussion that has come into play revolves around where hearing loss fits into those binary categories.  Sometimes a severely affected child may have multiple clinical sequelae (“symptomatic”) and have hearing loss (“symptomatic”) or may just have hearing loss (“asymptomatic”).

As an audiologist, I can definitely convey that hearing loss is significant so saying an infant is asymptomatic when they have hearing loss doesn’t sit well with me, and actually with many others.  That has led to some adding a third classification of “asymptomatic with hearing loss”.  We decided to not use any of these for public health case ascertainment by just having “infection” (laboratory evidence without clinical signs) and “disease” (laboratory evidence with clinical signs).  Infection means infected with CMV without known consequences; disease means infected with CMV with known consequences.
As for your question about older children, typically when an older infant or child gets investigated for a cCMV infection it would be because of a health or developmental concern consistent with cCMV that is either late-onset or late-identified.  In these instances, because they would already be over 21 days old, the only way to positively identify a cCMV infection would be by testing the dried blood spot taken at birth – if it had been kept in storage by the newborn screening program.  If the CMV PCR testing is positive on the dried blood spot and clinical criteria was met for the disease classification, the child would be classified as having cCMV disease if reported to public health.

7. How do you think this work will impact the future of congenital CMV research?
We think this will help to get the CMV community on the same page.  Researchers look to those of us in public health who are conducting disease surveillance.  It’s always helpful when comparing research studies if “cases” are determined by the same definitions.  Our clinical research partners look to us to collaborate on studies utilizing our collected public health data.

8. If families and professionals want to learn more about the position statement and the standardized case definitions for congenital CMV, where should they look?  

The position statement can be found on the CSTE website:
Type in 23-ID-02 into the Search bar or click here for the pdf.