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NEWSLETTER N°3 / May 2024
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Welcome to the
3rd Long COVID Newsletter!
The Long COVID project, a 4-year EU initiative coordinated by the Helsinki University Hospital (HUS), nearly crosses its halfway mark. Launched on June 1 2022, the consortium has been working together through nine interconnected work packages aimed to understand the mechanisms of host-virus response underlying the long-term symptoms following SARS-CoV-2 infection.
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This Newsletter provides an overview of the main progress on the project’s updates for the past months.
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Update from the different Work Packages
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Long COVID Cohorts
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The primary goal of WP1 “LCS cohorts and guidelines”, coordinated by HUS, is to study the clinical characteristics, prognosis, incidence, and healthcare burden of the Long COVID Syndrome (LCS). This is being accomplished through ongoing tasks by collecting data from both clinical and control cohorts in Finland (Registry linkage cohort from the Finnish National Centre for Health and Welfare, LC policlinic, ClinCOVID Cohort, ICU Cohort), Switzerland (Basel LC Syndrome Cohort BALCoS) and the Netherlands
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(Lifelines/ Dutch population cohort). Although there were some challenges with recruitment, the consortium has mitigated them promptly with a change in strategy. One publication was recently published describing the protocol of the Long COVID Cohort Study to assess the prognosis and prognostic determinants of patients with Long COVID by implementing patient-reported outcome measures, patient-reported experience measures and clinical examinations during a 1-year follow-up (Virrantaus et al., BMJ Open, 2023). All studies are ongoing at the moment and first results are expected at the end of 2024.
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Mechanistic and Pathogenic Studies
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The WP2, led by UH, focuses on identifying the potential mechanism underlying LCS and symptom-related changes. One major objective here is to study the dynamics of the immune responses and to identify factors critical for viral control and immune protection. Therefore, patient samples were collected and stored in the Helsinki biobank for subsequent analysis. The results from the serological analysis are expected to be published in summer 2024. To identify the impact of SARS-CoV-2 infection on the neuronal cells, a protocol was established to detect virus infection and the associated changes in neuronal culture. Significant progress was made in understanding SARS-CoV-2 interactions with neuron and glial cells with the novel "mini-brain" model where miniaturised brains are artificially created in the laboratory starting from human stem cells and can be infected with different viruses that have neuroinvasive potential (2nd Long COVID newsletter).
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Upcoming publications will describe in detail the discoveries made in the research associated with the mechanisms of neural infection and effective inhibitors.
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With mouse model experiments, led by UZH, the partners gained further insights into the pathomechanism of neural infection with different SARS-CoV-2 strains, such as Wuhan, Delta and Omicron isolates. The following questions are analysed:
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- Does SARS-CoV-2 generally spread to the brain in the mouse?
- Does SARS-CoV-2 persist in the brain?
- Can the spread of SARS-CoV-2 to the brain be blocked by anti-viral drugs?
- What are the effects of neuronal SARS-CoV-2 infection on the brain environment?
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New results from the mouse model experiments will soon be reported in scientific publications.
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LCS translational biomarker studies
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In WP3, coordinated by PROTOBIOS, the consortium will develop tools and methods for translating data into insights regarding immune system dynamics and the identification of biomarkers that are indicative of the progression of COVID-19 illness to LCS, by leveraging on genomics, lipidomics and immunomics. Currently, progress is made with ongoing sample collection, however, there is a challenge in recruitment due to the overall decline in COVID-19 cases. High throughput antibody response screening is set to discover disease mechanisms and novel biomarkers.
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LCS Intervention Studies
Study 1: AIR trial
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This study is carried out at the HUS LC Clinic and HUS Clinic for Functional Disorders to compare the AIR (Amygdala and Insula Retraining) program with an internet therapy developed at HUS for persistent somatic symptoms. The aim is to study what the effect of the AIR program and an Internet therapy on patients’ assessment of functional ability and quality of life as compare to treatment as usual. The trial will clarify whether internet-based non-drug therapies are helpful in overcoming the effects of autonomous nervous system dysregulations that many LC patients are suffering from. Intermediate analysis indicate that this study is progressing according to plan and a protocol paper for this study was already submitted to a peer-reviewed scientific journal.
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Study 2: DiLCoS
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At UNIBAS, a validation in the clinical setting study “Proof of Feasibility of a Digitally Blended Learning Healthcare System for LC Syndrome (DiLCoS)” is performed to develop and implement digitally blended interventions (‘digital therapeutics’) for LCS patients targeting established and newly identified risk factors and mechanisms detected within this consortium. The overarching aim of this intervention is to optimize neuroendocrine-immune responses against SARS-CoV-2 as well as to improve coping with burdening symptoms. For this study, extensive efforts were made to develop a dedicated platform for patients and clinicians, incorporating 123 intervention elements across 12 modules and 1 onboarding module (e.g., videos, interviews, exercises, quizzes). With a short delay, this study started in February 2024 and is currently ongoing.
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Biomarker Prediction and Patient Stratification
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This specific WP (WP5 led by partner NEC) is focused on the discovery of biomarkers and the stratification of patients using explainable AI models. In the last months, the consortium was successful in developing a multimodal data representation model that integrates various data types, offering comprehensive patient profiles.
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Data Portal
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One of the main objectives of the Long COVID project is the establishment of the open-access Long COVID Data Portal (LCDP) to collect the data for Long COVID Syndrome research, from the project but also from external sources. The technical team has successfully developed the first version of the LCDP with advanced data management interfaces and user-friendly data visualisation interfaces, including interactive infographics. These infographics will be continuously improved with outcomes from the study conducted by HUS to understand the impact of infographics in clinical settings.
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Ethics and Privacy
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Within the Long COVID project, partner Chino is the leader of WP7 “Ethics and privacy”. The main objectives of WP7 are: (1) Ethics – This consortium will invest significant effort to ensure all AI-based decision support developed in the project are ethical and trustworthy, this is especially important with AI and medical ethics that are based on the principle of “primum non nocere”—"first, do no harm”, (2) General Data Protection Regulations (GDPR) compliance – Need to demonstrate how the architecture developed is completely compliant with GDPR and that data is stored in a suitably robust manner, and Data security – Need to assure the data are managed in respect of the privacy regulations and security best practices.
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First milestones have been achieved by identifying which data should be shared among project partners, identifying the role of data processor and controllers, and by securing the necessary technical infrastructure for data sharing. To effectively achieve the goals, the consortium continuously keeps track of changes in the regulatory frameworks that govern data security and privacy, both at EU level and at the participating country level. In addition, WP7 is committed to the ethical development and use of AI-based decision support tools, by establishing an external ethics advisory board, which reviews the ethical dimensions of this project, aligning with the European commission guidelines and addressing medical ethics and trustworthy AI.
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Relationship between Epstein-Barr virus and SARS-CoV-2
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Estimates suggest that 2% to 7% of the population may be affected by Long COVID (LC). The Patient-Led Research Collaborative projects that 65 million individuals worldwide are dealing with this condition (1). The widespread impact of LC is evident, with millions of individuals globally affected by this challenging condition. The figures are concerning, highlighting the ongoing complexity of diagnosing and managing LC (2).
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LC is a condition with symptoms persisting for at least four weeks post-infection. It presents with over 200 symptoms and is diverse in nature. NIH study has classified LC into four subphenotypes in terms of the affected tissues: cardiac and renal (34% of patients); respiratory, sleep and anxiety (33%); musculoskeletal and nervous system (23%); and digestive and respiratory (10%) (3).
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Like other chronic conditions, the development LC involves a combination genetic and environmental factors that disrupt regular body functions, resulting in a chronic phase with relapses and incomplete recovery. This increased vulnerability to external triggers underscores the importance of thorough phenotyping and mechanistic investigations in current LC research to identify patients that may benefit from tailored treatment.
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A recent study found that individuals with persistent cognitive symptoms, commonly referred to as brain fog, following their initial COVID-19 infection showed gene signatures resembling those seen in acute infections (4). Additionally, LC patients exhibiting cognitive impairment and fatigue demonstrated increased levels of pNfL compared to those without these symptoms, positioning pNfL as a potential biomarker for ongoing central nervous system (CNS) injury in LC. These insights hold promise in enhancing our understanding of LC progression, shedding light on potential extensions of CNS damage, and the consequent neurodegenerative implications (5). The Attomarker test offers insights into antibody effectiveness against different variants of Covid, revealing that approximately 50% of LC patients exhibit suboptimal antibody responses.
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This inadequacy could predispose individuals to prolonged viral presence and heightened inflammatory reactions. Moreover, this in-depth analysis integrating complex datasets identified a consistent activation pattern involving myeloid cells and the complement system across various clinical subtypes. Particularly noteworthy was the sustained activation of these immune pathways in LC patients even post-recovery from acute Covid, indicating persistent inflammatory responses in this population (6). Finally, elevated levels of Epstein-Barr virus (EBV) have been observed in some individuals with LC (5), sparking interest due to EBV's association with chronic fatigue syndrome (7). Studies suggest that when individuals contract SARS-CoV-2, EBV may reactivate and proliferate at higher levels, potentially attributed to a heightened immune response in certain patients. While a correlation between EBV reactivation and long COVID has been noted (8-11), concrete evidence is currently limited. Nonetheless, active EBV infection could disrupt immune responses in LC through epigenetic pathways (8).
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Summary: LC presents diagnostic challenges due to its complexity and wide-ranging impact on physiological systems. Collaborative research endeavours such as the LONG COVID project, which combines multi-omics data integration with meticulous clinical assessments, play a vital role in advancing our comprehension of these complex interactions underlying the chronic condition.
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Registry Study: Epidemiology and commonness between Finland and Netherlands
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Objectives:
The aim of the register-based study was to observe the change in number of diagnosis possibly related to post COVID-19 conditions during the years 2019, 2020 and 2021 in Finland comparing to the similar general practice-based register data from the Netherlands. This comparison will help to identify some possible general similarities or differences between the data of the two countries. Furthermore, it will set a basis for further analyses on the linkage between acute COVID-19 and the incidence of symptoms related to post COVID-19 allowing for later analyses on the post COVID-19 condition burden of disease.
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The study is based on data obtained from the National Infectious Disease Register, the Care Register for Healthcare and the Primary Healthcare Visit Register (Finland), and the AHON-database (Netherlands). Persistent symptoms after COVID-19 infection were recognized and classified as “core”, “acute”, or “other” (figure 1).
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All data were derived separately for the years 2019, 2020 and 2021. Changes in numbers of set diagnoses were observed and compared. For this research, all data were pseudonymized (after register linkage and) before analyses.
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The Finish data show an increase in the number of individuals diagnosed with almost all core symptoms, a decrease was only observed in the umber of individuals diagnosed with “ageusia/anosmia”. The biggest changes between 2019 and 2021 were seen in “insomnia” (68%), “anxiety” (51%), “runny nose” (44%), “heavy arm and/or legs” (38%) and “general tiredness” (31%). By including occupational healthcare data the increase in post COVID-19 related symptoms between the years 2020-2021 was even larger: up to one third in “difficulties with breathing” and up to 2/3 and more in symptoms like “lump in throat”, “heavy legs and arms” and “painful muscles” and up to 90% in “tiredness”. Increase of 35% applied also to “ageusia/anosmia” diagnoses when occupational healthcare was included.
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The Dutch data show an increase in the number of individuals diagnosed with almost all symptoms defined as core symptoms of post COVID-19 condition, except for “general tiredness” that slightly decreased. The biggest changes in numbers of individuals with a certain diagnosis between years 2021 and 2019 are seen in the core symptoms of “tingling extremities” (27%), “ageusia/anosmia” (26%), and “lump in throat” (23%). When comparing 2020 with 2019, there was a remarkable increase in the core symptoms “pain when breathing” which was reduced to a 14% increase when comparing 2021 to 2019.
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Both in the Finnish and Dutch data, the core symptoms were increased when comparing 2021 registry data to 2019 registry data, the only exceptions being in Finland a 3% decrease in “ageusia/anosmia”, and in the Netherlands a 3% decrease in “feeling hot/cold alternately” and a 6% decrease in “general tiredness”. The largest differences between Finland and the Netherlands also occurred in these symptoms, with a 26% increase in “ageusia/anosmia” in the Netherlands, and a 31% increase in “general tiredness” in Finland. In contrast, the frequency of “difficulties with breathing”, “chest pain”, “lump in throat” and “tingling extremities” was remarkably similar in both countries, with differences of 0 to 4 percent points. Reasons for the differences between the countries could be (i) different coding systems for the symptoms in the countries and (ii) differences in health care seeking behaviour, related to specific symptoms.
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In any case, this study set basis for further analyses on the linkage between acute COVID-19 and the incidence of symptoms related to post COVID-19. Further questions the consortium wants to address are: Can a greater increase in the diagnoses related to post COVID-19 condition be observed in those diagnosed with acute COVID-19? At what point of time after an acute SARS-CoV-2 infection are the diagnoses set? Has the individual possibly had some of the diagnoses even before the pandemic and a possible SARS-CoV-2 infection?
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Figure 1: Persistent symptoms after COVID-19 infection were recognized and classified as “core”, “acute”, or “other”.
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Peer-reviewed Scientific Publications
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(1) Liira, H.; et al. Prognosis of patients with post-Covid-19 conditions: Prospective cohort cluster analysis at one year. J Psychosom Res. 2024. doi: 10.1016/j.psychores.2024.111808
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(2) Virrantaus, H.; et al. Prognosis of patients with long COVID symptomes: a protocol for a longitudinal cohort study at a primary care referred outpatient clinic in Helsinki, Finland. BMJ Open. 2023. doi:10.1136/bmjopen-2023-072935
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(3) De Neck, S.; et al. The Stereotypic Response of the Pulmonary Vasculature to Respiratory Viral Infections: Findings in Mouse Models of SARS-CoV-2, Influenza A and Gammaherpesvirus Infections. Viruses. 2023. doi: 10.3390/v15081637
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(4) Kettunen, P.; et al. SARS-CoV-2 Infection of Human Neurons Is TMPRSS2 Independent, Requires Endosomal Cell Entry, and Can Be Blocked by Inhibitors of Host Phosphoinositol-5 Kinase. Journal of Virology. 2023. doi: 10.1128/ivi.00144-23.
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These publications are also available on the Long COVID website and in the Long COVID community on Zenodo, a multi-disciplinary open repository.
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Long COVID Project Meetings
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The Long COVID consortium gathered again online on the 11th and 12th of January for the first consortium meeting in 2024. During these two days the consortium, comprised of dedicated partners, immersed themselves in a dynamic agenda focused on mutual updates, idea exchange, and engaging discussions to enhance the project’s progress. With a united commitment to success, participants delved deep into the specific tasks outlined in the various work packages. Next to the scientific topics, the consortium focused on the preparations for their first reporting.
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The technical and financial reports were submitted in January, followed by a successful review meeting on the 29th of January. After this review meeting, different deliverables were accepted by the Project Officer and can be found on the Long COVID Website:
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Upcoming Webinar: Unlocking the Mysteries of Long COVID: How EU Funding is Paving the Way for Recovery!
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Join us for an insightful webinar aimed at enhancing patient engagement within the framework of the Long COVID EU Project. Designed to foster collaboration and understanding, this webinar offers a unique opportunity for patients, caregivers, healthcare professionals, and researchers to come together and explore strategies for improved patient involvement in managing and understanding Long COVID.
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Learn more about the Long COVID EU Project and dive deeper into the following topics:
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(1) Does the COVID-19 virus infect our brain? What research are we doing?
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(2) What is the LongCOVID project about?
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(3) The Finnish Registry Study and
Velina Vangelova-Korpinen (HUS)
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Project Coordinator-Support
Riikka Paasikivi
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Communication & Dissemination leader
Lena Schleicher
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Funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency (HaDEA). Neither the European Union nor HaDEA can be held responsible for them.
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