Host RNA Expression Profiles and Protein Biomarkers in Neonatal Herpes Simplex Virus Infection

This study seeks to identify and test host RNA expression profiles in context to protein biomarkers in dried blood spot samples as novel diagnostic markers of neonatal herpes simplex virus infection and to improve the understanding of the pathogenesis of the disease.

Study Overview

• Status: Completed
• Conditions: Neonatal Infection; Viral Infection; Neonatal Sepsis; Neonatal Death; Herpes Simplex Virus Infection; Newborn; Infection; Neonatal Herpes Simplex Infection; Neonatal HSV Infection

Detailed Description

Background:

Herpes Simplex Virus (HSV) infection in newborns is uncommon but can be devastating and is associated with significant morbidity and mortality. The diagnosis of neonatal HSV infection is challenging because maternal genital herpes often is asymptomatic and the clinical presentation in newborns can be nonspecific, especially in the early disease stages. This results in late diagnosis and potentially terrible consequences for the newborn. The reason why some newborns develop severe disease due to HSV infection is unknown. It has been suggested that immunologic differences in early infancy are the key to further advances. Host RNA expression profiling, transcriptomics, of the host response to infections has shown great potential as clinical tool for diagnostics and for unveiling molecular disease mechanisms. As previously shown, reliable host RNA expression data can be obtained from neonatal dried blood spot (DBS) samples by RNA-sequencing. Proteomic analysis has the potential to simultaneously identify hundreds of protein biomarkers and immune cell populations allowing for detailed mapping of disease immunological pathways.

Method:

A nationwide retrospective case-control study of all newborns with HSV infection in Denmark from 2010 through 2019. DBS samples will be obtained from the Danish Neonatal Screening Biobank, Statens Serum Institut. RNA sequencing and proteomic analyses will be performed at the Danish Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institut. Cases will be randomly assigned to a "Discovery cohort" and compared to a control group of newborns matched on gestational age, sex and birthweight will be included.

Time frame:

Sample identification/recruiting: January 1st to January 31st 2022. Sample analysis (RNA sequencing and proteomic analysis): February 1st to April 30th 2022.

Perspectives:

New molecular-based diagnostic tools complementary to conventional methods may improve early diagnosis of neonatal HSV infections and lead to optimised management. In addition, 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 (Actual): 159

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Department of Paediatrics and Adolescent Medicine, Rigshospitalet
  • Copenhagen, Denmark, 2300
    • Department of Congenital Disorders, Statens Serum Institut

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 4 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Newborns aged 0-28 days with verified HSV infection in Denmark from 2010 through 2019.

Description

Inclusion Criteria:

1. cases of newborns aged 0-28 days with verified HSV infection (positive HSV PCR in blood, cerebrospinal fluid and/or swab sample)
2. controls of newborns without infection matched on gestational age, sex and birthweight

Exclusion Criteria:

1. dried blood spot samples that are not allowed to be used for research
2. dried blood spots samples containing insufficient amount of blood for research

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Cases; 54 newborns with neonatal HSV infection. Interventions: Diagnostic test and disease pathogenesis: Host RNA expression profiling by RNA sequencing and proteomic analyses. Cases will be randomly assigned to a "Discovery Cohort" (identification of diagnostic RNA and proteomic profiles).
Controls; 108 newborns without infection. Interventions: Diagnostic test and disease pathogenesis: Host RNA expression profiling by RNA sequencing and proteomic analyses. Controls will be randomly assigned to a "Discovery Cohort" (identification of diagnostic RNA and proteomic profiles).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Host RNA expression and proteomic profiles	To identify specific host RNA expression and proteomic profiles in dried blood spot samples from newborns with HSV infection	Admission, age 0-28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease pathogenesis	Mapping of disease immunological pathways by simultaneous host RNA expression profiling and proteomic analysis	Admission, age 0-28 days
Application of known host RNA profiles	To test host RNA profiles published in other studies, e.g. based on the genes IFI44L and FAM89A	Admission, age 0-28 days

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): January 1, 2022
• Primary Completion (Actual): February 28, 2022
• Study Completion (Actual): April 30, 2022

Study Registration Dates

• First Submitted: January 27, 2022
• First Submitted That Met QC Criteria: January 27, 2022
• First Posted (Actual): February 7, 2022

Study Record Updates

• Last Update Posted (Estimate): December 28, 2022
• Last Update Submitted That Met QC Criteria: December 25, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Infant, Newborn, Diseases; DNA Virus Infections; Sepsis; Skin Diseases, Infectious; Skin Diseases, Viral; Pregnancy Complications; Death; Herpesviridae Infections; Infections; Communicable Diseases; Virus Diseases; Herpes Simplex; Pregnancy Complications, Infectious; Perinatal Death; Neonatal Sepsis
• Other Study ID Numbers: H-21009288-HSV

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