Occurrence of Antibodies Cross-reacting With Autoantigens in Primary EBV Infection

Occurrence of Antibodies Cross-reacting With Autoantigens in Primary EBV Infection - a Longitudinal, Observational Study

The aim of this study is to assess the occurrence of antibodies cross-reacting with autoantigens that have been detected in the context of SLE in patients with primary EBV infection over time compared to a control group. It is to establish a biobank of patients with primary EBV infection allowing to longitudinally analyze the immune response and its accompanying inflammatory processes with focus on the occurrence of antibodies cross-reacting with autoantigens associated with SLE and other autoimmune diseases.

Substudies will analyze

• characteristics of primary EBV infection patients treated with antibiotics in comparison to patients treated without antibiotics and outcomes of these treatment regimens (occurrence of acute complications such as peritonsillar abscess (PTA) or need for tonsillectomy, frequency of fatigue or symptoms associated with chronic fatigue syndrome).
• Procalcitonin (PCT) concentrations in primary EBV infection compared to control patients with similar symptoms and its association with disease severity and local complications.
• the occurrence of fatigue and symptoms associated with chronic fatigue syndrome 6 and 12 months after primary EBV infection.

Study Overview

• Status: Recruiting
• Conditions: Epstein-Barr Virus (EBV) Infection
• Intervention / Treatment: Other: Data collection: Participant characteristics (Illness course, complications of primary EBV infection and provided treatments); Other: Data collection: blood samples (analysed for EBV serology, auto-antibody-testing/biobanking, RNA expression analyses, procalcitonin); Other: Data collection: Patient reported outcome (Fatigue questionnaires)

Detailed Description

Epstein-Barr Virus (EBV) is a lymphotropic herpes virus and the causative agent of infectious mononucleosis (IM). The course of EBV infection is determined by the virus load and an individuals' immune system state, which in turn is determined by the person's gene composition, other infection history and several environmental factors, which all may influence the immune capacity of a person to various degrees. Many diseases are known to be associated with EBV infection, among those diseases are systemic autoimmune diseases. With regard to EBV, prior infection with the virus seems to be of crucial importance for the development of systemic lupus erythematosus (SLE). Autoantibodies against complement C1q (anti-C1q) can be induced in vivo by the Epstein-Barr virus-derived antigenic site 'EBNA348' (also being part of the C-terminal EBNA-1).

This study is to analyze whether the primary infection with EBV (leading to IM and antibodies targeting EBV-derived antigens including antibodies against EBNA-1) leads to an at least transient occurrence of antibodies against the virus that have the potential to cross-react with autoantigens as described in patients with systemic autoimmune diseases (e.g. complement C1q, dsDNA, Ro, Sm, MOG, NF186 and others). The advantage of an analysis of patients with primary infection is that the de novo synthesis of antibodies against the virus will allow to determine the time-dependent evolution of the antibody repertoire against the virus as well as against a number of autoantigens.

• Study Type: Observational
• Enrollment (Estimated): 80

Contacts and Locations

• Study Contact: Name: Samuel Etienne; Phone Number: +41 61 556 5248; Email: samuel.etienne@usb.ch
• Study Contact Backup: Name: Michael Osthoff, PD Dr. med.; Phone Number: +41 61 328 68 28; Email: michael.osthoff@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • Recruiting
    • University Hospital Basel, Division of Internal Medicine
    • Contact: Samuel Etienne; Phone Number: +41 61 556 5248; Email: samuel.etienne@usb.ch
    • Sub-Investigator: Marten Trendelenburg, Prof. Dr. med.
    • Contact: Michael Osthoff, PD Dr. med.; Phone Number: +41 61 328 68 28; Email: michael.osthoff@usb.ch
    • Principal Investigator: Michael Osthoff, PD Dr. med.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Inpatients and outpatients with symptoms of infectious mononucleosis (IM) or a sore throat who are treated at the University Hospital of Basel will be approached.

Description

Inclusion Criteria:

Participants fulfilling all of the following inclusion criteria are eligible for the infectious mononucleosis (IM) group:

• Informed consent as documented by signature
• Confirmed primary EBV infection as confirmed by the treating clinician and defined by:
• Compatible clinical (infectious mononucleosis symptoms including but not limited to malaise, headache, fever, tonsillitis, pharyngitis, cervical lymph nodes enlargement) and laboratory picture (lymphocyte count elevation, LUC cells, reactive lymphocytes in manual differential, elevated liver enzymes; of note, not all typically described features have to be fulfilled)

AND

• serology compatible with primary EBV infection (anti-EBNA IgG negative, anti-VCA IgG negative, anti-VCA IgM positive OR anti-EBNA IgG negative, anti-VCA IgG positive, anti- VCA IgM positive).

Participants fulfilling all of the following inclusion criteria will be eligible for the control group:

• Informed consent as documented by signature.

• one of the following:

  1. Clinical picture of upper respiratory tract infection (including but not limited to tonsillitis/pharyngitis, malaise, headache, cough, rhinitis, cervical node enlargement)
  2. confirmed primary Cytomegalovirus (CMV) infection (an optimal control group; however, the number of patients with a diagnosis of primary CMV infection is limited).

Exclusion Criteria:

• Suspicion/diagnosis of IM as per judgement of the treating clinician (control group only); this individual may be eligible later for the IM group if primary EBV infection is confirmed, subsequently.
• Immunosuppression (broadly defined as primary/secondary immunodeficiency or treatment with an immunosuppressive medication including ≥ 10mg prednisone equivalent).
• History of autoimmune disease (e.g. SLE, vasculitis etc.)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
patients with confirmed primary EBV infection; 40 patients with confirmed primary EBV infection as confirmed by the treating clinician and defined by: - Compatible clinical (infectious mononucleosis symptoms including but not limited to malaise, headache, fever, tonsillitis, pharyngitis, cervical lymph nodes enlargement) and laboratory picture (lymphocyte count elevation, LUC cells, reactive lymphocytes in manual differential, elevated liver enzymes; of note, not all typically described features have to be fulfilled) AND - serology compatible with primary EBV infection (anti-EBNA IgG negative, anti-VCA IgG negative, anti-VCA IgM positive OR anti-EBNA IgG negative, anti-VCA IgG positive, anti- VCA IgM positive)	Other: Data collection: Participant characteristics (Illness course, complications of primary EBV infection and provided treatments); Data collection: Participant characteristics (Illness course, complications of primary EBV infection and provided treatments) during 12 months (baseline visit and follow-up visits at 3, 6 and 12 months).; Other: Data collection: blood samples (analysed for EBV serology, auto-antibody-testing/biobanking, RNA expression analyses, procalcitonin); Data collection: blood samples (analysed for EBV serology, auto-antibody-testing/biobanking, RNA expression analyses, procalcitonin) during 12 months (baseline visit and follow-up visits at 3, 6 and 12 months).; Other: Data collection: Patient reported outcome (Fatigue questionnaires); Data collection: Patient reported outcome (Fatigue questionnaires) at 6 and 12 months.
control patients; 40 control patients (Clinical picture of upper respiratory tract infection (including but not limited to tonsillitis/pharyngitis, malaise, headache, cough, rhinitis, cervical node enlargement)) and/ or confirmed primary Cytomegalovirus (CMV) infection	Other: Data collection: Participant characteristics (Illness course, complications of primary EBV infection and provided treatments); Data collection: Participant characteristics (Illness course, complications of primary EBV infection and provided treatments) during 12 months (baseline visit and follow-up visits at 3, 6 and 12 months).; Other: Data collection: blood samples (analysed for EBV serology, auto-antibody-testing/biobanking, RNA expression analyses, procalcitonin); Data collection: blood samples (analysed for EBV serology, auto-antibody-testing/biobanking, RNA expression analyses, procalcitonin) during 12 months (baseline visit and follow-up visits at 3, 6 and 12 months).; Other: Data collection: Patient reported outcome (Fatigue questionnaires); Data collection: Patient reported outcome (Fatigue questionnaires) at 6 and 12 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in occurrence of antibodies cross-reacting with autoantigens in patients with primary EBV infection	Change in occurrence of antibodies cross-reacting with autoantigens in patients with primary EBV infection compared to a control group.	at Visit 2 (day 1 (+ 1 day)), Visit 3 (3 months +/- 21 days), Visit 4 (6 months +/- 1 month) and Visit 5 (12 months +/-2 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in RNA expression profiles of peripheral blood cells	Change in RNA expression profiles of peripheral blood cells in patients with primary EBV infection over time and compared to a control group.	at Visit 2 (day 1 (+ 1 day)), Visit 3 (3 months +/- 21 days), Visit 4 (6 months +/- 1 month) and Visit 5 (12 months +/-2 months)
Change in Fatigue Assessment Scale (FAS)	The total score ranges from 10 to 50. A total FAS score < 22 indicates no fatigue, a score ≥ 22 indicates fatigue.	at month 6 and at month 12
Change in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) questionnaire	FACIT-F is a 13-item instrument designed to assess fatigue/ tiredness and its impact on daily activities and functioning in a number of chronic diseases. The instrument includes items such as tiredness, weakness, listlessness, lack of energy, and the impact of these feelings on daily functioning (e.g., sleeping, and social activities). Items are scored on a 0 - 4 response scale with anchors ranging from "Not at all" to "Very much so" (in which higher scores represent better functioning or less fatigue).	at month 6 and at month 12
Change in Procalcitonin (PCT) (Substudy Procalcitonin)	Change in PCT compared in primary EBV infection patients with different disease severities and different treatment modalities (in particular if they received antibiotics or not), and in comparison to a control group (with mostly (viral) upper respiratory tract infection or primary CMV infection); In IM and control patients admitted to hospital, blood will be collected for PCT measurement	on day 1 and day 3 (+/-1 day)
Occurrence of acute complications such as PTA or need for tonsillectomy	Occurrence of acute complications such as PTA or need for tonsillectomy in primary EBV infection patients treated with antibiotics in comparison to patients treated without antibiotics	at Visit 2 (day 1 (+ 1 day)) and Visit 3 (3 months +/- 21 days),

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Michael Osthoff, PD Dr. med., University Hospital Basel, Division of Internal Medicine

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: October 25, 2021
• First Submitted That Met QC Criteria: November 8, 2021
• First Posted (Actual): November 19, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 24, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Systemic lupus erythematosus (SLE); Infectious mononucleosis (IM); Viral capsid antigen (VCA); EBV nucleic antigen (EBNA); Chronic fatigue syndrome (CFS); cross-reacting antibodies; molecular mimicry
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Virus Diseases; DNA Virus Infections; Herpesviridae Infections; Tumor Virus Infections; Infections; Communicable Diseases; Epstein-Barr Virus Infections; Immunologic Factors; Physiological Effects of Drugs; Antibodies; Autoantibodies
• Other Study ID Numbers: 2021-01338; am21Osthoff2

Drug and device information, study documents

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