Epigenetic Changes in Long COVID Patients

NCT07757620 | Not Yet Recruiting

• 1 other identifier: ECLIPSE - CTSPV86-25
• Study Type: observational
• Target: 1,000
• Locations: 1 country
• Sites: 3

Brief Summary

The goal of this observational study is to improve the understanding of the biological mechanisms underlying long COVID and to identify molecular biomarkers that may support its diagnosis, prognosis, and future precision medicine approaches in adults with long COVID, adults who have fully recovered from COVID-19, and healthy control participants. The main questions it aims to answer are:

• What molecular, immunological, epigenetic, and microbiome profiles distinguish individuals with long COVID from recovered COVID-19 participants and healthy controls?
• How are viral persistence, immune dysregulation, and alterations in the gut-immune axis associated with the development and clinical manifestations of long COVID?
• Which molecular biomarkers may improve disease diagnosis, patient stratification, and the identification of potential therapeutic targets? Participants will:
• Undergo clinical evaluation and provide information about their medical history and symptoms.
• Provide biological samples, including blood and, when clinically indicated, intestinal biopsy tissue collected during routine colonoscopy procedures.
• Undergo comprehensive molecular analyses, including immunological, epigenetic, transcriptomic, proteomic, and microbiome profiling.
• Have their clinical and molecular data integrated using advanced computational approaches to identify biological signatures associated with long COVID. The results of this study may improve the understanding of the biological mechanisms underlying long COVID and support the development of novel biomarkers and future precision medicine approaches for diagnosis, prognosis, patient stratification, and therapeutic target identification.

Conditions

Long COVID-19 Syndrome; Long COVID Symptoms

Keywords

Long COVID-19; COVID-19; gut; Chronic inflammation; epigenetics; methylation; omics; artificial intelligence; ai; machine learning; Multi-omics approaches; biomarker; Immune aging; genomics; transcriptomics; spatial omics; epigenomics; cytokines

Outcome Measures

Primary Outcomes (3)

• Gene expression profile of peripheral blood cells

  Transcriptomic profiling will be performed in peripheral blood leukocytes using RNA sequencing. Gene expression will be expressed as normalized gene expression counts. Differential transcript abundance will be compared across participants with Long COVID with cardiopulmonary manifestations, Long COVID without cardiopulmonary manifestations, COVID-19 participants without persistent sequelae, and pre-pandemic healthy controls.

  Baseline

• DNA methylation profile of peripheral blood cells

  Genome-wide DNA methylation will be measured using the EPIC-v2 array and/or whole-genome bisulfite sequencing. Results will be expressed as DNA methylation β-values or methylation percentages (%). Methylation profiles will be compared across study groups.

  Baseline

• Frequency of peripheral blood immune cell populations

  Frequency of circulating immune cell subsets will be measured by multiparameter flow cytometry. Results will be expressed as the percentage (%) of the parent cell population. The analyses will include investigation of CD4+ T cells, CD8+ T cells, NK cells, B cells and regulatory T cells. Immune profiles will be compared among study groups.

  Baseline

Secondary Outcomes (2)

• Chromatin accessibility in peripheral blood leukocytes

  Baseline

• Gut microbiome composition

  Baseline

Other Outcomes (1)

• Predictive performance of integrated multi-omic models

  Baseline through 12 months

Study Arms (3)

Post COVID-19 patients

Retrospective cohort of subjects that manifested COVID-19 and recovered without sequelae. Inclusion criteria: * Age ≥ 18 years. * Previous SARS-CoV-2 infection documented by molecular or serological testing. * Absence of persistent symptoms 2 months after acute infection. * Willingness to provide written informed consent.

Long COVID-19 patients

Retrospective and prospective cohorts of patients that manifested COVID-19 and developed sequelae. The retrospective cohort includes subjects with long COVID-19 with or without cardiac symptoms. The prospective cohort includes patients with long COVID-19 and gastrointestinal symptoms. Inclusion criteria: * Age ≥ 18 years. * Previous SARS-CoV-2 infection documented by molecular or serological testing. * Persistent symptoms at least 2 months after acute infection, according to the WHO definition of long COVID \[https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition\]. * Willingness to provide written informed consent.

Control Group

Retrospective cohort of subjects who never had SARS-CoV-2 infection. Inclusion criteria: * Age ≥ 18 years. * No previous SARS-CoV-2 infection (documented by serology). * Blood sample collected according to the COVID-BioVac protocol (NCT05276388) before the first administration of the SARS-CoV-2 vaccine. * Willingness to provide written informed consent.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Post COVID-19 patients: Retrospective population of patients that manifested COVID-19 and recovered without sequelae. Long COVID-19 patients: Retrospective and prospective populations of patients that manifested COVID-19 and developed sequelae. The retrospective cohort includes subjects with long COVID-19 with or without cardio-pulmonary symptoms. The prospective cohort includes patients with long COVID-19 and gastrointestinal symptoms. Control Group: Retrospective population of subjects who never had SARS-CoV-2 infection.

You may qualify if:

• Age ≥ 18 years.
• Previous SARS-CoV-2 infection documented by molecular or serological testing.
• Absence of persistent symptoms 2 months after acute infection.
• Willingness to provide written informed consent.
• Age ≥ 18 years.
• Previous SARS-CoV-2 infection documented by molecular or serological testing.
• Persistent symptoms at least 2 months after acute infection, according to the WHO definition of long COVID \[https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition\].
• Willingness to provide written informed consent.
• Age ≥ 18 years.
• No previous SARS-CoV-2 infection (documented by serology).
• Blood sample collected according to the COVID-BioVac protocol (NCT05276388) before the first administration of the SARS-CoV-2 vaccine.
• Willingness to provide written informed consent.

You may not qualify if:

• Inability to provide informed consent.
• Presence of severe systemic autoimmune diseases or congenital/acquired immunodeficiencies that may confound the interpretation of immunological data.
• Current systemic immunosuppressive therapy or treatment within the last 6 months prior to enrollment.
• Active malignancies or those treated within the last 12 months (except basal or squamous cell carcinomas in situ).
• Pregnancy or breastfeeding at the time of enrollment.
• Any other clinical condition that, in the investigator's opinion, could compromise the reliability of the data collected.

Sponsors & Collaborators

• Istituti Clinici Scientifici Maugeri SpA: lead
• IRCCS Ospedale San Raffaele: collaborator
• Istituto Auxologico Italiano: collaborator

Study Sites (3)

Istituto Auxologico Italiano

Cusano Milanino, Milano, 20095, Italy

Location

Ospedale San Raffaele S.r.l.

Milan, 20132, Italy

Location

Istituti Clinici Scientifici Maugeri

Pavia, 27100, Italy

Location

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Related Links

• Post COVID-19 condition (Long COVID): brief description by the WHO of Long COVID

Biospecimen

Retention: SAMPLES WITH DNA

* Plasma * Peripheral Blood Mononuclear cells * DNA * RNA * Gut biopses

MeSH Terms

Conditions

Post-Acute COVID-19 Syndrome; COVID-19

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Post-Infectious Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Carlo Gaetano, Professor

CONTACT

+390382592262; carlo.gaetano@icsmaugeri.it

Michela Gottardi Zamperla, PhD

CONTACT

+390382593563; michela.gottardizamperla@icsmaugeri.it

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: OTHER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 30, 2026
• First Posted: August 11, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: August 11, 2026

Record last verified: 2026-08

Locations

IT (3)