The Role of Obesity in Severe COVID-19 Pathophysiology

NCT ID: NCT06968442

Last Updated: 2025-05-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-04-22
• Study Completion Date: 2026-04-22

Brief Summary

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide. As of 2024, the SARS-CoV-2 Omicron variant is the predominant strain circulating within the population, generally causing mild upper respiratory tract infections. However, hospitalizations and case fatalities due to COVID-19 continue, and there is a high probability that a new human coronavirus will emerge in the future. Understanding the pathophysiology of severe COVID-19 remains highly relevant, as its mechanisms may be comparable to those of other respiratory viral infections.

SARS-CoV-2 infects human cells primarily by binding to angiotensin-converting enzyme 2 (ACE2) and type 2 transmembrane serine protease (TMPRSS2) receptors, which are both expressed in alveolar epithelial type II cells, through the virus' spike protein. In a later stage, the replication of SARS-CoV-2 and activation of resident immune cells lead to the infiltration and activation of large numbers of innate immune cells. Consequently, this results in an excessive pro-inflammatory immune response, including increased production of IL-6, a hallmark cytokine of severe COVID-19. Eventually, the excessive inflammation results in microthrombus formation and pulmonary edema.

Further studies have indicated that SARS-CoV-2 spike-specific antibodies, along with alveolar macrophages, play a pivotal role in the pathophysiology of severe COVID-19. Alveolar macrophages, which reside in the lung alveoli, are typically the first immune cells to sense pulmonary pathogens. However, these cells can also bind IgG antibodies through their Fc-receptor, leading to cellular activation. When stimulated with both a viral stimulus and anti-SARS-CoV-2 IgG antibodies from severe COVID-19 patients (a situation similar to that in the lungs of these patients) alveolar macrophages elicit a significant proinflammatory response. This response aligns with the observed post-seral conversion deterioration in COVID-19 patients.

Obesity is a significant risk factor for developing severe COVID-19, but the underlying mechanism is not well understood. Previous studies report that macrophages in obese patients are skewed towards a pro-inflammatory phenotype due to altered fatty acid contents, particularly increased saturated fatty acids. Using our in vitro obesity model, which incorporates higher saturated fatty acid contents, the investigators already demonstrated that SARS-CoV-2 antibody-mediated inflammation of alveolar macrophages is increased (unpublished data). Thus, this may explain why obese patients are more likely to develop severe COVID-19.

To validate these in vitro findings, the investigators aim to confirm these results in monocyte-derived macrophages isolated from individuals with and without obesity. Additionally, the investigators will investigate the underlying mechanisms involved in detail. This study will provide valuable insights into the role of obesity in severe COVID-19 and potentially inform therapeutic strategies for at-risk populations.

Detailed Description

This is a mono-center, prospective cohort study involving both a test group and a control group. The test group comprises patients with obesity eligible for bariatric surgery at Franciscus Hospital, while the control group consists of age- (maximum 5-year difference) and sex-matched non-obese healthcare workers at Franciscus Hospital. Blood samples will be collected from all participants at a single time point.

Obese patients will be approached for informed consent during their intake appointments, typically weeks to months before their bariatric surgery. Blood samples will be collected before surgery or during surgery to minimize any potential adverse effects. Collaborating researchers from the surgery department will manage the inclusion of obese patients and coordinate their blood collection.

For the non-obese control group, investigators from MMI will manage participant inclusion and blood sample collection.

Participants from Franciscus Hospital with obesity (Cohort 1) and healthcare workers without obesity (Cohort 2) will undergo a single venipuncture after an 8-hour fasting period. A total of 40 mL of blood will be collected in four 10 mL EDTA tubes.

At the Medical Microbiology and Infection Control (MMI) laboratory of Franciscus, blood samples will be collected after which these are sent to the Center for Infection and Molecular Medicine (CIMM) laboratory in Amsterdam UMC. Here, blood will be processed (i.e., isolation of plasma, monocytes, and remaining peripheral blood mononuclear cells (PBMCs)), where after monocytes will be put into culture to become monocyte-derived macrophages. Macrophage stimulations and additional macrophage analyses will be performed at Amsterdam UMC. Data obtained from analyses in Amsterdam UMC will be further analyzed in Amsterdam UMC by coordinating investigator Ashwin Mak (who is also affiliated at CIMM in Amsterdam UMC) and co-investigator Dr. Jeroen den Dunnen. Monocytes and plasma will be stored in Amsterdam UMC until the end of this study, where after the remaining materials will be transported to Franciscus.

Isolated PBMCs and plasma will be transported in the following days after isolation to Franciscus MMI for T cell stimulations and antibody analyses. In the analyses overview below, the location where each analysis will be performed is noted (i.e., MMI and CIMM). Coded samples and data will be stored at Amsterdam UMC until the end of this study, where after these samples are destroyed and data are deleted. MTA and DTA documents will be prepared for the transfer of blood and data to Amsterdam UMC.

Conditions

COVID-19; Antibody COVID-19

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

General

The intervention is a blood collection, whereafter blood will be analyzed for immunological parameters.

Group Type: OTHER

Venipuncture

Intervention Type: PROCEDURE

Simple blood collection

Interventions

Venipuncture

Simple blood collection

Intervention Type: PROCEDURE

Other Intervention Names

Venapuncture; Blood collection

Eligibility Criteria

Inclusion Criteria

Cohort 1 (obesity cohort)

• ≥18 and ≤65 years of age
• BMI ≥30 kg/m²
• Patient of Franciscus Hospital

Cohort 2 (control cohort)

• ≥18 and ≤65 years of age
• BMI <25 kg/m²
• Healthcare workers of Franciscus Hospital

Exclusion Criteria

• Acute infection or current systemic immunological disorders
• Use of immune-modulatory medication (i.e., corticosteroids and biologicals)
• Hormonal therapy

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Franciscus Gasthuis

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David S.Y. Ong, M.D., Ph.D., Pharm.D., M.Sc.

Role: PRINCIPAL_INVESTIGATOR

Franciscus Hospital

Locations

Franciscus

Rotterdam, South Holland, Netherlands

Site Status: RECRUITING

Countries

Netherlands

Central Contacts

Willem A Mak, M.Sc.

Role: CONTACT

ashwinmak98@gmail.com

+316 40897778

References

Hoepel W, Chen HJ, Geyer CE, Allahverdiyeva S, Manz XD, de Taeye SW, Aman J, Mes L, Steenhuis M, Griffith GR, Bonta PI, Brouwer PJM, Caniels TG, van der Straten K, Golebski K, Jonkers RE, Larsen MD, Linty F, Nouta J, van Roomen CPAA, van Baarle FEHP, van Drunen CM, Wolbink G, Vlaar APJ, de Bree GJ, Sanders RW, Willemsen L, Neele AE, van de Beek D, Rispens T, Wuhrer M, Bogaard HJ, van Gils MJ, Vidarsson G, de Winther M, den Dunnen J. High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages. Sci Transl Med. 2021 Jun 2;13(596):eabf8654. doi: 10.1126/scitranslmed.abf8654. Epub 2021 May 11.

Reference Type: BACKGROUND

PMID: 33979301 (View on PubMed)

Other Identifiers

NL88800.100.25

Identifier Type: -

Identifier Source: org_study_id