The Role of Obesity in Severe COVID-19 Pathophysiology

NCT06968442 | Recruiting

• 1 other identifier: NL88800.100.25
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

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.

Conditions

COVID-19; Antibody COVID-19

Keywords

COVID-19; Obesity; Antibodies; Macrophages; Immunity; Fc receptors

Outcome Measures

Primary Outcomes (1)

• The concentration of pro-inflammatory cytokines (IL-6, IL-1β, and TNF) produced by macrophages upon both SARS-CoV-2 viral and antibody costimulation.

  Monocytes will be isolated from blood of participants of both groups, whereafter these are differentiated into macrophages. These macrophages will be stimulated with a virus and SARS-CoV-2 IgG combined stimulation. After the stimulation, the concentration of pro-inflammatory cytokines is measured in the supernatant of the macrophages.

  Baseline

Secondary Outcomes (10)

• The concentration of pro-inflammatory cytokines (IL-6, IL-1β, and TNF) produced by macrophages upon separate viral stimulation or SARS-CoV-2 antibody stimulation

  Baseline

• The plasma concentration of pro-inflammatory cytokines

  Baseline

• Measurement of other cytokines that are produced by macrophages upon viral stimulation, antibody stimulation, or both

  Baseline

• Expression levels of Fc receptors on the surface of macrophages

  Baseline

• The level of intracellular lipids in monocytes

  Baseline

Study Arms (1)

General

OTHER

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

Procedure: Venipuncture

Interventions

Venipuncture PROCEDURE

Simple blood collection

Also known as: Venapuncture, Blood collection

General

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Franciscus Gasthuis: lead

Study Sites (1)

Franciscus

Rotterdam, South Holland, 3045PM, Netherlands

RECRUITING

Related Publications (1)

• 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.

  PMID: 33979301 BACKGROUND

MeSH Terms

Conditions

COVID-19; Obesity

Interventions

Phlebotomy; Blood Specimen Collection

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; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Therapeutics; Surgical Procedures, Operative; Investigative Techniques

Study Officials

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

  Franciscus Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Willem A Mak, M.Sc.

CONTACT

+316 40897778; ashwinmak98@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The investigators include a cohort of obesity patients (all BMI \>35) who are eligible for bariatric surgery and a control cohort of age and sex matched lean (all BMI \<25) healthcare workers. From all individuals, blood is collected and immunological analyses are performed.

Study Record Dates

• First Submitted: April 28, 2025
• First Posted: May 13, 2025
• Study Start: April 22, 2025
• Primary Completion: December 31, 2025
• Study Completion: April 22, 2026
• Last Updated: May 16, 2025

Record last verified: 2025-04

Locations

NL (1)