Nine researchers from the Amsterdam Institute for Immunology and Infectious diseases (AI&I) have collectively secured €6.5 million in ZonMw grants for post-COVID research. The researchers, Brent Appelman and Prof. Dr. Joost Wiersinga, Prof. Dr. Michèle van Vugt, Dr. Pythia Nieuwkerk, Dr. Sander Verfaillie, Dr. René Lutter, Dr. Jos Bosch, Dr. Amélie Bos, and Dr. Jeroen den Dunnen, will conduct both clinical and fundamental research. The funding supports various clinical trials, PET scans, neuro-imaging and stimulation, and the establishment of in vitro models all focused on post-COVID. Together with the recently opened post-COVID Center of Expertise at Amsterdam UMC, this substantial funding strengthens the leading role of Amsterdam UMC and AI&I in post-COVID research.
Overview of research projects
Brent Appelman and Prof. Dr. Joost Wiersinga – TURN-Long COVID Study
The cause of post-COVID remains unknown, and its presentation is heterogeneous. Recently, Brent Appelman, Prof. Wiersinga and colleagues have identified autoantibodies in post-COVID patients that target the body’s own tissues, which may classify post-COVID as an autoimmune disease. To test this hypothesis, the TURN-Long COVID study proposes using immunoadsorption to filter out these autoantibodies. The study is a randomized, placebo-controlled proof-of-concept clinical trial, that will evaluate immunoadsorption’s effects, Brent Appelman, Prof. Wiersinga and colleagues received €1.268.643 from ZonMw to conduct the TURN-Long COVID study.
Brent Appelman explains: "In the TURN-Long COVID study, we will screen participants for autoantibodies using a new diagnostic tool, enrolling only those with pathogenic antibodies. This precision-based immunotherapy could help clarify the role of autoantibodies in post-COVID and open the door to other therapies, such as rituximab, daratumumab, efgartigmod, FcRn inhibitors, and intravenous immunoglobulin (IVIG)."
Prof. Dr. Michèle van Vugt – Sonlicromanol in Post-COVID
The Phase 2 study of Prof. Dr. Michèle van Vugt, received €992.633 from ZonMw to conduct the double-blind, placebo-controlled trial, designed to evaluate whether sonlicromanol can mitigate mitochondrial dysfunction’s cytotoxic effects, which may underlie post-COVID symptoms. This trial will yield early insights into the drug’s effectiveness for this new application. The trial will be conducted in collaboration with Khondrion, a clinical-stage biopharmaceutical company with a focus on discovering and developing therapies targeting mitochondrial disease.
Prof. Dr. Michèle van Vugt, project leader of the post-COVID Center of Expertise at Amsterdam UMC, comments: “Post-COVID symptoms can be life-altering, significantly impacting quality of life. We hope that sonlicromanol will ease these burdens, improving the lives of those affected.”
Dr. Pythia Nieuwkerk – sElective Serotonin reuPtake inhibitoRs In posT-covid: ESPRIT
Dr. Pythia Nieuwkerk has been awarded €955,632 by ZonMw to conduct a placebo-controlled clinical trial investigating the effectiveness of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine in reducing post-COVID symptoms. Fatigue, cognitive problems, post-exertional malaise (PEM), and postural orthostatic tachycardia syndrome (POTS) are common and debilitating symptoms of post-COVID, yet the pathophysiology remains poorly understood, and no established biomedical treatments exist. Thus, effective treatment options are urgently needed.
Fluvoxamine, an SSRI, is a promising candidate for reducing post-COVID symptoms due to its regulatory effects on the (neuro)immune system, the hypothalamic-pituitary-adrenal (HPA) axis, and the tryptophan system. In collaboration with the Post COVID Network Netherlands, Dr. Nieuwkerk and colleagues will randomize 160 participants to receive either fluvoxamine or a placebo for 12 weeks.
Dr. Pythia Nieuwkerk: “We will employ advanced neuroimaging techniques during cognitive challenges and analyze plasma biomarkers (inflammatory markers, cortisol, serotonin, and IDO-2 activity) to uncover potential mechanistic pathways for post-COVID treatment. If fluvoxamine proves effective in reducing post-COVID symptoms, it could be an important extension of treatment options for post-COVID patients.”
Dr. Sander Verfaillie - Mitigating Cognitive Problems and Fatigue with Brain Stimulation in Post-COVID
Dr. Sander Verfaillie has been awarded €894.937 to conduct a randomized trial examining whether non-invasive brain stimulation (rTMS) can alleviate cognitive problems and severe fatigue in post-COVID patients. These symptoms are common and can greatly disrupt daily life, yet their underlying mechanisms remain unclear. Previous research indicates that post-COVID may be associated with reduced brain blood flow and neuroinflammation, which could explain these symptoms. Non-invasive brain stimulation has been safely and effectively used in other conditions to address similar symptoms. When combined with MRI, this technique enables highly precise targeting of specific brain areas, allowing for a personalized approach to treatment.
Dr. Sander Verfaillie stated: “Non-invasive brain stimulation holds great promise as a treatment to reduce disabling cognitive symptoms in post-COVID patients and offers a unique opportunity to identify the neurobiological mechanisms that contribute to symptom relief”
Dr. René Lutter – Targeting IDO2 Activity in Post-COVID
René Lutter leads two projects focused on the enzyme IDO2 in Post-COVID:
Clinical Trial to Inhibit IDO2 Activity in Post-COVID
Dr. Lutter’s previous research has linked prolonged IDO2 expression and activity in blood and brain tissue from post-COVID patients to mitochondrial dysfunction. Other researchers have shown that the kynurenine metabolites correlate with cognitive symptoms, post-exertional malaise and inflammation in post-COVID. Thus, it is likely that IDO2 underlies symptomology in post-COVID. Dr. Lutter received €399.170 from ZonMw for this small intervention trial where they will repurpose a safe drug that also inhibits IDO2 activity, to explore efficacy, optimal dosing and treatment duration, with plans to expand to a larger study, potentially including children with post-COVID.
The IDO2-kynurenine Pathway in Post-COVID: from Diagnostics to Who is at Risk
A better understanding of the regulation of IDO2 expression and activity and the downstream kynurenine pathway in post-COVID can lead to the identification of diagnostic markers for post-COVID and explain why a SARS CoV2 infection leads to post-COVID in some individuals only. Awarded €410.925 by ZonMw, this project aims to uncover diagnostic markers for post-COVID by studying genetic factors that influence IDO2 expression and the kynurenine pathway, comparing post-COVID patients with fully recovered individuals. Findings could improve diagnostic tools and risk assessment, especially for children and ME/CFS patients.
Dr. Jos Bosch - A Mechanism-based Approach to the Assessment and Diagnosis of Orthostatic Intolerance in Post-COVID
Orthostatic Intolerance (OI), characterized by symptoms like dizziness and fainting upon standing, affects an estimated 30-70% of post-COVID patients. Standard diagnostic tests provide limited information to guide treatment decisions, leaving even those with severe symptoms undiagnosed or inadequately treated. Previous findings indicate that nearly all patients with OI symptoms show reduced cerebral blood flow, likely underlying their symptoms. Awarded €710.796 by ZonMw, this project will conduct three interlinked studies to explore autonomic-cardiovascular, neurobiological, and autoimmune mechanisms to improve diagnostic precision and clinical care.
Dr. Jos Bosch, lead investigator of the National post-COVID cohort and biobank, explains: “For many post-COVID patients, debilitating symptoms are met with inconclusive tests and limited treatment options. Our research aims to close this gap by identifying mechanisms of orthostatic intolerance, providing a clearer path towards more accurate diagnoses and personalized care.”
Dr. Amélie Bos - Pathophysiology of Post-COVID Autoantibodies on Mitochondria-Mediated Muscle and Neuron Function
Dr. Bos's study, awarded €491.779 from ZonMw, aims to develop lab models that replicate post-COVID. By introducing patient-derived antibodies into cell cultures, the researchers will observe how specific post-COVID autoantibodies affect cell function, focusing on mitochondrial pathways. Using human skeletal muscle, heart, and neuron cultures, they will pinpoint binding sites of post-COVID autoantibodies and examine impact on metabolism, calcium signaling, and muscle contraction. This research could reveal disease mechanisms, support patient subgroup classifications, and lead to drug screening applications.
Dr. Jeroen den Dunnen – PET Scans for Microclots
Dr. Jeroen den Dunnen was awarded € 308.716 for his research into PET Scans for Microclots. Post-COVID patients have high levels of microclots, protein clumps that may harm blood vessels in tissues. However, where these microclots accumulate in the body is mostly unknown. This project will use full-body PET scans to locate these microclots in post-COVID patients.
Linking new projects to previous findings by AI&I researchers
In previous projects, AI&I researchers identified two major biomedical abnormalities in post-COVID patients: metabolic dysregulation, mainly due to dysfunctional mitochondria, and autoimmunity, with patients producing self-targeting antibodies causing symptoms like pain and fatigue. The current grants allow the five awarded AI&I researchers to translate these findings into clinical practice, with trials to counteract autoimmunity or mitochondrial dysfunction.
What can we expect when we look ahead?
Autoimmunity treatment: To address the complexities of autoimmunity, our AI&I researchers will investigate immune adsorption. This method aims to remove IgG antibodies, including harmful autoantibodies, from the blood to see if it reduces symptoms in post-COVID patients. If successful, this could support broader use of IgG-suppressing drugs for post-COVID.
Metabolism treatment: Our AI&I researchers will explore drugs that support mitochondrial function, such as sonlicromanol, or inhibit IDO2 activation. These treatments have the potential to restore metabolic function and provide relief for patients suffering from symptoms like post-exertional malaise.
Pharmacological treatment: To explore effective pharmacological options for post-COVID, our AI&I researchers will investigate the potential of selective serotonin reuptake inhibitors (SSRIs), particularly fluvoxamine, in alleviating debilitating symptoms. By regulating the (neuro)immune system, hypothalamic-pituitary-adrenal (HPA) axis, and tryptophan system, SSRIs may offer relief for post-COVID patients and they can be an important treatment extension.
Advancements in diagnostics and classification: To enhance understanding of post-COVID our AI&I researchers will focus on innovative diagnostics. They will utilize total-body PET scans, various neuro-imaging and stimulation methods, in vitro models, and studies of genetic polymorphisms related to the IDO2-kynurenine pathway. These approaches will provide new insights into post-COVID’s pathophysiology, aiding in the categorization of patient subtypes and potentially leading to the identification of biomarkers. Additionally, the in vitro assays will facilitate the screening of patients for the immunoadsorption trial, effectively connecting foundational research with practical therapeutic applications.
Amsterdam UMC researchers involved
TURN-Long COVID Study
Brent Appelman1,8,9, MSc, PhD-candidate
Joost Wiersinga1,8, Professor of Internal medicine and head of infectious diseases
Michèle van Vugt1,2,9, Professor of Internal medicine and chair post-COVID center of expertise
Liffert Vogt2,3, Professor of Clinical nephrology and renal physiology
Jeroen den Dunnen1,8, PhD, Immunologist
Dominque Baeten, Professor of Rheumatology
Hessel Peters-Sengers1, PhD, Clinical epidemiologist
Amélie Bos1,8, PhD, Immunologist
René Lutter1,15, PhD, Immunologist and biochemist
Marie José Kersten1,4, Professor of hematology
Jarom Heijmans4,5, PhD, Apheresis specialist
Casper de Boer6, PhD, Senior data steward
Sonlicromanol in Post-COVID
Michèle van Vugt1,2,8, Professor of Internal medicine and chair post-COVID center of expertise
Brent Appelman1,8,9, MSc, PhD-candidate
sElective Serotonin reuPtake inhibitoRs In posT-covid : ESPRIT
Pythia Nieuwkerk1,2,16, PhD, Senior researcher
Christiaan Vinkers2,6,18, PhD, Professor of Psychiatry
Jantine Colen-de Koning19, PharmD, PhD, Hospital Pharmacist
Guido van Wingen6,18, PhD, Professor of Brain Imaging
Sander Verfaillie1,2,6,16,18, PhD, Neuropsychologist
Hans Knoop2,4,16, PhD, Professor of Medical Psychology
Charlotte Teunissen6,20, PhD, Professor in Neurochemistry
Jos Bosch1,2,16,17, PhD, Medical Psychology, project leader Netherlands post-COVID cohort and biobank
Neeltje Kootstra1,2, PhD, Associate Professor Experimental Immunology
Maria Prins1,2,9, PhD, Professor of Public Health and Infectious Diseases
Frederik Barkhof4,6,21, PhD, Professor of Neuroradiology
Menno de Jong1,22, PhD, Professor of Clinical Virology
Mitigating Cognitive Problems and Fatigue with Brain Stimulation in Post-COVID
Sander Verfaillie1,2,6,16,18, PhD, Neuropsychologist
Odile van den Heuvel6, PhD, Professor of neuropsychiatry
Ysbrand van der Werf6, PhD, Professor of Neuroanatomy
Jos Bosch1,2,16,17, PhD, Medical Psychology, project leader Netherlands post-COVID cohort and biobank
Guido van Wingen6,18, Professor of Neuroimaging in Psychiatry
Charlotte Teunissen6,20, Professor in Neurochemistry
Frederik Barkhof4,6,21, Professor of Neuroradiology
Michèle van Vugt1,2,9, Professor of Internal medicine and chair post-COVID center of expertise
Willem de Haan23, PhD, Neurologist and senior researcher
Anna Wojdala6,20, PhD, senior researcher neurochemistry
Pythia Nieuwkerk1,2,16, PhD, Senior researcher
Anouk Schrantee6,11, PhD, assistant professor Radiology & Nuclear Medicine
Henk-Jan Mutsaerts6,11, PhD, assistant professor Radiology & Nuclear Medicine
Targeting IDO2 Activity in Post-COVID
René Lutter1,15, PhD, Immunologist and biochemist
Brent Appelman1,8,9, MSc, PhD-candidate
Michèle van Vugt1,2,9, Professor of Internal medicine and chair post-COVID center of expertise
Riekelt Houthooper3,7,10, Professor of Translational Metabolism
Fred Vaz2,5,10, PhD, Clinical Biochemist
Michel van Weeghel3,5,10, PhD, Manager Core Facility Metabolomics
Jan Booij6,11, Professor of Experimental Nuclear Medicine
Jan Willem Duitman1,4,12, PhD, Assistent professor
Annemiek Dijkhuis1,12, MSc
Study 2: The IDO2-kynurenine Pathway in Post-COVID: from Diagnostics to Who is at Risk
René Lutter1,15, PhD, Immunologist and biochemist
Brent Appelman1,8,9, MSc, PhD-candidate
Michèle van Vugt1,2,9, Professor of Internal medicine and chair post-COVID center of expertise
Riekelt Houthooper3,7,10, Professor of Translational Metabolism
Fred Vaz2,5,10, PhD, Clinical Biochemist
Michel van Weeghel3,5,10, PhD, Manager Core Facility Metabolomics
Marianna Bugiani4,6, PhD, senior pathologist, expert brain pathology
Wilma van de Berg6, PhD, Senior Neuroscientist
A Mechanism-Based Approach to the Assessment and Diagnosis of Orthostatic Intolerance in Post-COVID
Jos Bosch1,2,16,17, PhD, Medical Psychology, project leader Netherlands post-COVID cohort and biobank
Jeroen den Dunnen1,8, PhD, Immunologist
Sander Verfaillie1,2,6,16,18, PhD, Neuropsychologist
Michèle van Vugt1,2,9, Professor of Internal medicine and chair post-COVID center of expertise
Frederik de Lange3, PhD, Professor of Cardiology
Guido van Wingen6,18, PhD, Professor of Brain Imaging
Shuxin Zhang16, PhD, Fair data manager
Rick Quax15, PhD, data scientist
Pathophysiology of Post-COVID Autoantibodies on Mitochondria-Mediated Muscle and Neuron Function
Amélie Bos1,8, PhD, Immunologist
Jeroen den Dunnen1,8, PhD, Immunologist
Brent Appelman1,8,9, MSc, PhD-candidate
Suzanne Terheggen-Lagro14, PhD, pediatric pulmonologist
Chen (Oliver) Hung-Jen1,3,8, PhD, postdoctoral scientist
Elga de Vries3,6, Professor of Neuro-immunology
PET Scans for Microclots
Jeroen den Dunnen1,8, PhD, Immunologist
Brent Appelman1,8,9, MSc, PhD-candidate
Chen (Oliver) Hung-Jen1,3,8, PhD, postdoctoral scientist
1Institute for Immunology and Infectious diseases (AI&I), Amsterdam UMC, the Netherlands
2Amsterdam Public Health (APH), Amsterdam UMC, the Netherlands
3Amsterdam Cardiovascular Sciences (ACS), Amsterdam UMC, the Netherlands
4Cancer Center Amsterdam (CCA), Amsterdam UMC, the Netherlands
5Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam UMC, the Netherlands
6Amsterdam Neuroscience (ANS), Amsterdam UMC, the Netherlands
7Amsterdam Reproduction and Development (AR&D)
8Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, the Netherlands
9Internal Medicine Department, Amsterdam UMC, the Netherlands
10Genetic Metabolic Diseases Department, Amsterdam UMC, the Netherlands
11Radiology Department, Amsterdam UMC, the Netherlands
12Department of Experimental Immunology, Amsterdam UMC, the Netherlands
13Pathology department, Amsterdam UMC, the Netherlands
14Paediatric Pulmonology, Amsterdam UMC, the Netherlands
15 Department of Respiratory Medicine, Amsterdam UMC, the Netherlands
16Department of Medical Psychology, Amsterdam UMC, the Netherlands
17Department of Psychology, University of Amsterdam, the Netherlands
18Department of Psychiatry, Amsterdam UMC, the Netherlands
19Knowledge center for drug research, Amsterdam UMC, the Netherlands
20Clinical Chemistry - Neurochemical Lab, Amsterdam UMC, the Netherlands
21Department of Radiology and Nuclear Medicine, Amsterdam UMC, the Netherlands
22Medical Microbiology & Infection prevention, Amsterdam UMC, the Netherlands
23Amsterdam Alzheimer Center, Amsterdam UMC, The Netherlands
Text: Esmée Vesseur