Protein Biomarkers and Host RNA Expression Profiles in Congenital Cytomegalovirus Infection

This study seeks to identify and test host protein biomarkers and RNA expression profiles in dried blood spot samples as novel diagnostic markers of congenital cytomegalovirus sequelae and to improve the understanding of the pathogenesis of the disease.

Study Overview

• Status: Recruiting
• Conditions: Sensorineural Hearing Loss; Congenital Cytomegalovirus; Cytomegalovirus Infections; Neonatal Infection; Viral Infection

Detailed Description

Background:

Human cytomegalovirus (CMV) is one of the most common causes of congenital viral infection, leading to a significant number of children with permanent disabilities. It is recognized as the major infectious cause of sensorineural hearing loss (SNHL) and neurodevelopmental abnormalities in infants. Its pathogenesis is largely unknown due to the complex interplay between viral, maternal, placental, and child factors. In Western Europe the incidence is estimated to 0.5-0.7% of all live births. In Denmark there are 240-480 children born every year with CMV infection, but the incidence has not been studied since 1979. Among the congenitally infected infants, approximately 10% are estimated to have symptoms at birth, ranging from mild, such as petechiae, to severe, such as microcephaly. Approximately half of these symptomatic children develop permanent long-term disabilities, such as hearing loss, cognitive and motor developmental delay. Asymptomatic children are also at risk for CMV-related disabilities, and 10-15% will develop SNHL. SNHL after congenital CMV infection may be present at birth or occur later in childhood and therefore, a significant part of these will not be detected in time for diagnosis and appropriate treatment, e.g., ganciclovir within the first 30 days of life. At present, there is no reliable virological marker to determine which infants will develop sequelae.

Method:

A nationwide retrospective case-control study of all neonates with congenital CMV infection in Denmark from 2010 through 2025. DBS samples will be obtained from the Danish Neonatal Screening Biobank, Statens Serum Institut. Proteomic analyses and RNA sequencing will be performed at the Department for Congenital Disorders, Statens Serum Institut. Cases will be randomly assigned to a "Discovery cohort" and compared to a control group of neonates matched on gestational age, sex, birthweight and age at DBS sample collection.

Perspectives:

New molecular-based diagnostic tools may contribute to improve early diagnosis and treatment of infants with congenital CMV infection and potentially prevent development of sequelae. Additionally, understanding of the pathogenesis at a molecular level of severe disease manifestations of the disease, could form the basis for development of novel interventions for better prevention and treatment.

• Study Type: Observational
• Enrollment (Estimated): 630

Contacts and Locations

• Study Contact: Name: Kia Hee Schultz Dungu, MD; Phone Number: +45 22645782; Email: kia.hee.schultz.dungu@regionh.dk
• Study Contact Backup: Name: Ulrikka Nygaard, Ass Prof PhD; Phone Number: +45 35459761; Email: Ulrikka.Nygaard@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Department of Paediatrics and Adolescent Medicine, Rigshospitalet
    • Contact: Kia Hee Schultz Dungu, MD; Phone Number: +45 22645782; Email: kia.hee.schultz.dungu@regionh.dk
  • Copenhagen, Denmark, 2300
    • Recruiting
    • Department of Congenital Disorders, Statens Serum Institut
    • Contact: David M Hougaard, D.Sc (med); Phone Number: +45 32683544; Email: dh@ssi.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study population consists of children born in Denmark between January 1, 2010 and December 31, 2025 with available neonatal dried blood spot samples collected through the Danish National Newborn Screening Program. The study includes children with verified congenital cytomegalovirus (CMV) infection and matched controls without congenital CMV infection. Children with congenital CMV infection will be categorized according to the presence or absence of CMV-associated sequelae based on clinical follow-up data.

Description

Inclusion Criteria:

1. Children born between 1 January 2010 and 31 December 2025 with an available neonatal dried blood spot sample collected through the Danish National Newborn Screening Program.
2. Cases: children with verified congenital CMV infection, defined as a positive CMV PCR result on neonatal dried blood spot, blood, or urine collected within the neonatal period.
3. Controls: children without evidence of congenital CMV infection selected from the same newborn screening population and matched to cases on sex, gestational age, birthweight, and age at DBS sampling.

Exclusion Criteria:

1. DBS samples not approved for research use.
2. DBS samples with insufficient blood material for RNA expression profiling and/or proteomic analyses.
3. Samples with inadequate analytical quality for molecular or proteomic analyses.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Cases; 300 children with symptomatic congenital CMV infection. Study procedures: Diagnostic/prognostic test and disease pathogenesis: Host RNA expression profiling by RNA sequencing and proteomic analyses. Cases will be randomly assigned to a "Discovery Cohort" for identification of diagnostic/prognostic RNA and proteomic profiles). Disease pathogenesis: Host RNA expression profiling by RNA sequencing and proteomic analyses will be performed to explore disease pathogenesis.
Control group 1; 300 children without congenital CMV infection. Study procedures: Diagnostic/prognostic test and disease pathogenesis: Host RNA expression profiling by RNA sequencing and proteomic analyses. Cases will be randomly assigned to a "Discovery Cohort" for identification of diagnostic/prognostic RNA and proteomic profiles). Disease pathogenesis: Host RNA expression profiling by RNA sequencing and proteomic analyses will be performed to explore disease pathogenesis.
Control group 2; 30 neonates with asymptomatic congenital CMV infection and no sequelae Study procedures: Diagnostic/prognostic test and disease pathogenesis: Host RNA expression profiling by RNA sequencing and proteomic analyses. Cases will be randomly assigned to a "Discovery Cohort" for identification of diagnostic/prognostic RNA and proteomic profiles). Disease pathogenesis: Host RNA expression profiling by RNA sequencing and proteomic analyses will be performed to explore disease pathogenesis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differential protein expression associated with sequelae following congenital cytomegalovirus infection	Normalized protein expression levels measured by Olink proteomics in neonatal dried blood spot samples obtained at birth from children with congenital cytomegalovirus infection who subsequently developed sequelae compared with children who did not develop sequelae and healthy controls.	At neonatal dried blood spot sampling (typically 2-3 days after birth).
Differential host RNA expression associated with sequelae following congenital cytomegalovirus infection	Host RNA expression profiles measured in neonatal dried blood spot samples obtained at birth from children with congenital cytomegalovirus infection who subsequently developed sequelae compared with children who did not develop sequelae and healthy controls.	At neonatal dried blood spot sampling (typically 2-3 days after birth).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune pathway enrichment based on proteomic and RNA expression profiles	Immune and inflammatory pathways will be assessed by host RNA expression and normalized protein expression levels measured in neonatal dried blood spot samples. Pathway enrichment analyses will be used to identify biological pathways associated with congenital cytomegalovirus infection and subsequent sequelae. Exploratory comparisons will be made with previously published host RNA expression signatures related to infectious disease and immune responses.	At neonatal dried blood spot collection (typically 2-3 days after birth).

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Collaborators: Statens Serum Institut
• Investigators: Principal Investigator: Kia Hee Schultz Dungu, MD, Rigshospitalet, Denmark; Study Chair: Ulrikka Nygaard, Ass Prof PhD, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2026
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: April 18, 2023
• First Submitted That Met QC Criteria: June 4, 2026
• First Posted (Actual): June 9, 2026

Study Record Updates

• Last Update Posted (Actual): June 9, 2026
• Last Update Submitted That Met QC Criteria: June 4, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Infections; DNA Virus Infections; Otorhinolaryngologic Diseases; Sensation Disorders; Ear Diseases; Herpesviridae Infections; Hearing Loss; Hearing Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Virus Diseases; Hearing Loss, Sensorineural; Cytomegalovirus Infections
• Other Study ID Numbers: H-21009288-CMV

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No