ORCHESTRA at ECCMID: latest insights on COVID-19's long-term effects
With over 13,000 participants each year, ECCMID acts as a vital platform for specialists from diverse fields to present their latest research and experiences in these areas. “For our team, participating in ECCMID is essential for fostering new partnerships”, Evelina Tacconelli, ORCHESTRA project coordinator, says. “This year, ORCHESTRA is privileged to contribute 13 distinct research outputs to the conference's agenda, focusing on a diverse range of topics. Notably, two of these contributions have been selected for oral presentation; one of them underscores our innovative approach to analysing the risk factors and determinants of post-acute sequelae of SARS-CoV-2 infection, commonly referred to as post-COVID syndrome (PCS)”.
The presentations and posters will delve into several critical topics addressed by the ORCHESTRA project over the course of its 3-year duration: the exploration of the SARS-CoV-2 virus's mutations and their practical implications in guiding vaccine and therapeutic developments; the understanding of PCS and the importance of chronic inflammation in its progression, offering new pathways for patient management and treatment; the impact of COVID-19 on women; vaccine efficacy in people with HIV; the gut microbiota's role in COVID-19 severity and the development of PCS; the design of clinical trials for PCS and the necessity of establishing a Cohort Coordination Board.
Intra-host mutations of SARS-CoV-2 spike protein have implication for research and treatment
Since it first appeared in late 2019, the virus that causes COVID-19 has been changing. These mutations help the virus spread more easily, infect more effectively, and dodge the body's immune defences. ORCHESTRA has investigated these mutations. “Our research looked at how the virus mutated over two years, focusing on areas of the virus's genetic code that changed a lot. We noticed that the mutation rates varied across different parts of the virus and between variants, like Delta and Omicron”, Mathias Smet from the University of Antwerp in Belgium explains, referring to the poster Quasi-species prevalence and evolution of mutations in SARS-CoV-2 variants in European COVID-19 cohorts. “We found many of these important mutations in the Spike protein – this is the part of the virus that helps it enter our cells and is a key target for vaccines and treatments. But mutations in other parts of the virus are also important for how the virus copies itself and evades the immune system”.
Knowing where these mutations tend to happen can help scientists focus on the most critical areas when designing new medications or vaccines. “This diversity, including fewer common variants, could affect how well treatments and vaccines work. Therefore, it's essential for scientific studies to include these variations to get a full picture of the evolution of the virus. As the virus changes, our approaches to dealing with it, including public health strategies, vaccine development, and treatments, need to adapt as well. By understanding where and how the virus is likely to mutate, we can be better prepared for future changes and ensure that vaccines and treatments remain effective”.
The external validity of prognostic COVID-19 scores is variable
The poster "External validations of prognostic COVID-19 scores – an innovative mass validation using the multi-center ORCHESTRA cohort" showcases a study focused on validating COVID-19 prognostic scores for routine medical use, to offer crucial insights for decision-makers and set the stage for enhanced pandemic readiness. These scores serve as clinical decision-making tools, routinely employed by healthcare professionals as "prediction rules" to mitigate severe health outcomes by adjusting treatments based on assessed risks. The research assessed the generalizability of these prognostic scores for both acute phase outcomes of COVID-19 such as mortality and also exploratory for the post-COVID Syndrome (PCS). Katharina Appel, a research associate at the University Hospital Cologne, notes concerns about bias, stating, "Most scores did not consistently meet the necessary quality standards and cannot be considered safe for the prognosis of acute phase outcomes, as demonstrated in our validation study. However, some scores designed to predict mortality merit further investigation." Regarding PCS, the variability in its clinical manifestations and severities complicates the creation of precise prognostic scores from acute phase data. Appel highlights: "The investigated scores were initially crafted to forecast outcomes in the acute phase, not PCS, and the exploratory assessment for the prognosis of PCS demonstrated limited effectiveness in this role."
Post-COVID syndrome depends on chronic inflammation and its symptoms are linked to the acute disease
PCS is a multifaceted condition that impacts various organs and body systems. ORCHESTRA used extensive datasets to explore the multifactorial impacts on the population, employing cutting-edge machine learning and artificial intelligence methodologies to elucidate these dynamics.
The team demonstrated that several and different biological mechanisms define the broad manifestations of PCS that can last years, even though they stem from the same initial infection.
In the presentation Latent Transition Analysis accurately describes post-COVID condition dynamics: at 3, 6, 12, and 18 months. Results from the Orchestra prospective international cohort, Anna Gorska from University of Verona will describe that PCS symptoms can change over time. “We think PCS symptoms come from various hidden phenotypes, each linked to different biological reasons”, Gorska says. “For example, being older, needing oxygen therapy, and obesity are linked to the respiratory type of PCS; our analysis suggested that the risk factors mainly affect the type of symptoms seen at the beginning, and not the changes between types later on. This supports our belief that the PCS type is set during the initial, acute phase of the disease”. The group of researchers found that at the last follow-up time point of 24 months, 22% of patients still experienced symptoms of PCS.
The poster Bio-humoral characterization of patients with post-COVID syndrome and its different clusters during acute infection and 18-months follow-up: The ORCHESTRA long-term sequelae study shows that several blood test abnormalities can be found during acute infection and that there are differences in inflammation markers in patients with PCS compared with those without PCS, in both acute COVID-19 infection and during follow-up, suggesting that chronic inflammation is an important characteristic of PCS. “During acute infection, a reduction of lymphocytes, platelets, and albumin values was observed, while lactate dehydrogenase, C-reactive protein, procalcitonin, ferritin, fibrinogen, glucose, and liver function tests increased. After the acute infection, these values normalize. It is interesting to note that several of these alterations are associated with the development of PCS. For example, patients who developed PCS with chronic pain were found to have had higher levels of lactate dehydrogenase, an inflammatory marker, during acute infection. Predictive value of acute infection features, including blood test alteration, may be key to tailoring the appropriate management for patients with PCS”, the infectious diseases specialist from University of Verona explains.
Women experience more work-related breakthrough infections and post-COVID syndrome
ORCHESTRA explored the interaction over time among the long-term sequelae of COVID-19. Notably, in the healthcare workers cohort, females, especially nurses, have been confirmed to experience a higher incidence of breakthrough infections compared to their male counterparts and other healthcare professions, according to a study whose poster will be presented by Giuseppe Delvecchio (SARS-CoV-2 breakthrough infections in healthcare workers of an Italian university hospital: an update 3 years after the start of the vaccination campaign).
Another study underlined that women also present a higher probability of developing PCS overall.
And a significant prevalence of neurosensorial post-COVID syndrome (researchers identified PCS clusters including respiratory, chronic pain, chronic fatigue, and neurosensorial issues), has been detected especially among women, as will be presented with the poster Neurosensorial cluster of the post-COVID-19 syndrome: prospective psychophysical assessment of smell and taste function and impact on quality of life. “Sex hormones and genetic factors have been proposed to explain the stronger humoral and cellular response observed in females compared to males”, Elisa Gentilotti explains. “Differences in the immune response could also affect the pathogenesis of PCS and neurosensorial symptoms and explain the higher prevalence observed among women”. The study investigated the smell and taste problems associated with (PCS) using a detailed sensory test. Compared to many studies relying on data from questionnaires filled out by participants themselves, this approach helped understand the various ways these senses are affected and sheds light on the biological reasons behind these changes.
COVID-19 vaccines show high level of induced immune response in people living with HIV
ORCHESTRA is one of the globe's largest and most comprehensive cohort platforms targeting several at-risk populations, including people living with HIV. The poster by University of Verona, Anti-RBD IgG titres after a primary vaccination course with BNT162b2 and after a third booster dose with a first-generation m-RNA vaccine in a cohort of people living with HIV, presents how HIV impacts vaccine-induced immunity: 97% of people living with HIV develop significant immune responses to the first course of COVID-19 mRNA vaccine, but the strength of this response depends on their immune health before vaccination, measured by CD4 T-lymphocyte counts. Those with higher CD4 counts (>500) have stronger responses than those with lower counts (<500).
“But even if the vaccine isn't updated for new variants, a booster dose increases antibody levels regardless of their CD4 count before vaccination”, Anna Maria Azzini reports. This suggests that boosters are particularly beneficial for enhancing immunity in people with HIV, including those with weaker immune systems. “While vaccination and boosters may not prevent infection completely, they help prevent severe illness”. These insights suggest that focusing on regular updates to match circulating variants and considering the immune status of individuals could be key strategies for future vaccine development and booster recommendations for this population.
Gut dysbiosis can predict COVID-19 severity and it is related to post-COVID syndrome
“Among our key findings is the elucidation of SARS-CoV-2’s impact on the intestinal microbiome presenting novel insights that bear significant implications for the development of new pharmacological strategies against SARS-CoV-2 and potentially other viral pathogens”, the coordinator of ORCHESTRA Evelina Tacconelli says. Two posters will focus on this topic: The gut microbiota as an early predictor of COVID-19 severity, and Longitudinal shifts in gut microbiota during mild COVID-19 are linked to Post-COVID-19 Syndrome.
In the first poster, Marco Fabbrini from Bologna University will present a machine learning tool that can predict COVID-19 severity from studying gut microbiota, with an accuracy rate of 81.5%; the tool holds promise for implementation in healthcare settings. “The significant variations in microbial diversity associated with COVID-19 severity observed in our study reveal a profound interplay between the gut microbiota and disease progression”, Fabbrini explains. “Individuals with severe COVID-19 exhibit dysbiosis, characterized by reduced diversity in the gut microbiota. This reduction in diversity can lead to impaired immune function, heightened inflammation, and altered metabolism, all of which may contribute to the severity of the disease. Moreover, specific microbial shifts, such as increases in opportunistic pathogens and decreases in beneficial bacteria, further exacerbate these effects. Understanding these variations offers valuable insights into potential therapeutic targets to mitigate COVID-19 severity and improve patient outcomes”.
The second poster highlights how specific mechanisms underlie the observed association between changes in gut microbiota composition during acute mild COVID-19 and the subsequent development of PCS: “The connections identified between the composition of gut microbiota during acute mild COVID-19 and the development of Post COVID Syndrome suggest a more pronounced dysbiosis, favouring opportunistic pathogens such as members of the bacterial family Enterobacteriaceae and the genera Streptococcus and Coprobacillus”, Marco Fabbrini says. “Specifically, a higher level of Coprobacillus at later stages of infection, lasting longer than three weeks, has been positively associated with the development of PCS at 6- and 12-months post-infection. These findings, coupled with the positive correlations observed between these bacterial taxa and blood inflammatory biomarkers, suggest that a prolonged inflammatory state possibly exacerbated or sustained by gut microbiota dysbiosis may contribute to the onset of PCS mechanisms.” This research opens new pathways for potential therapeutic interventions targeting gut microbiota to mitigate the impacts of COVID-19, especially the post COVID syndrome. “We propose interventions that could be managed by general practitioners and be easily accessible to the public. In this regard, microbiota-targeted interventions could focus on enhancing the maintenance of a healthy state by providing probiotic strains and prebiotics. These interventions aim to support the population of fiber-fermenting bacteria in our gut, which we found to be reduced during the acute phase of COVID-19. Additionally, maintaining a diverse and healthy diet could further contribute to strengthen the gut epithelium and promote the production of immune-modulating metabolites, such as short-chain fatty acids that, in turn, may enhance gut barrier function and potentially mitigate inflammation”.
Cohorts show power to inform clinical trials for post-COVID syndrome
Despite a wealth of research, a shortage of therapeutic measures designed to prevent and treat PCS and its associated clinical groupings remains. Randomized clinical trials (RCTs) play a crucial role in determining the effectiveness of potential treatment approaches. The poster Driving selection of target populations to design RCT assessing therapies for the prevention and treatment of the post-COVID-19 syndrome presents the study in which OCHESTRA identifies a target population for RCTs based on known risk factors of PCS and clinical severity of COVID-19. “The analysis of the ORCHESTRA cohort suggests that the target populations for PCS prevention should always consider obesity, chronic obstructive pulmonary syndrome, and embolic pulmonary complication as risk factors and should consider variants of concern and gender in the RCT design”, the researcher Elisa Gentilotti says.
The Cohort Coordination Board: combining forces to improve Europe's preparedness plans
The work of ORCHESTRA underscores the necessity for interdisciplinary cooperation throughout the European scientific community, bringing together stakeholders, researchers, and projects in a unified endeavour to learn from the COVID-19 pandemic. This spirit of collaboration is essential in enhancing the readiness and response strategies for upcoming infectious disease challenges. In the presentation Supporting synergies across cohort research projects for optimal and more rapid evidence generation: the case of the Cohort Coordination Board (CCB) Evelina Tacconelli will explain what the COVID-19 Coordination Board is. “This board includes representatives from the European Commission, major stakeholders, patient organizations, and the principal investigators of ongoing cohort-based research projects in Europe, initially focused on COVID-19. We are now expanding our scope to include other significant infectious diseases, such as monkeypox and sexually transmitted diseases, and we plan to extend our efforts to additional infectious diseases. The goal is to create a framework where key decisions about research during pandemic times can be made, ensuring we are not caught unprepared. The importance of our activities during inter-pandemic periods cannot be overstated”, Evelina Tacconelli says.
ORCHESTRA presence and participation at ECCMID reflects the unwavering commitment to advancing the frontiers of infectious diseases research. With its contribution, ORCHESTRA aspires to foster a deeper understanding of the infectious disease dynamics, enhance global health security, and pave the way for innovative treatments and preventive measures.
Information based on a press release by the ORCHESTRA project, 24 April 2024 (further information about ORCHESTRA).
The Division of Infectious Diseases and Tropical Medicine at the LMU University Hospital Munich is a project partner of ORCHESTRA.
The ORCHESTRA (orchestra-cohort.eu), coordinated by Prof. Tacconelli and the team of the University of Verona, is funded by the European Union’s Horizon 2020 research and innovation programme and started on December 2020 with the aim of tackling the coronavirus pandemic. The project involves 37 partners from 15 countries, establishing an international large-scale-cohort to generate rigorous evidence in the field of prevention and treatment of SARS-CoV-2 infection. The identification of clinical and laboratory predictors to reduce severity and hospitalization of COVID-19 and to prevent long COVID are among the main objectives of the project.
Learn more about the collaboration and the project.
The ORCHESTRA project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101016167. The views expressed in this publication are the sole responsibility of the author and the Commission is not responsible for any use that may be made of the information it contains.
