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Long COVID-19 syndrome and impact on patients' lives: new study from ORCHESTRA

A new study from the ORCHESTRA project identifies four different clinical phenotypes of long COVID-19 syndrome and their impact on patients' lives. Protective role of vaccination, monoclonal antibodies and corticosteroids confirmed.

Study published in the journal eClinical Medicine DOI: (https://doi.org/10.1016/j.eclinm.2023.102107)



The ORCHESTRA project, coordinated by the University of Verona and funded by the European Union's Horizon 2020, presents in the prestigious journal eClinical Medicine the results of a prospective cohort study following up for 12 months 1800 patients to understand the determinants and clinical presentations of the so-called 'long COVID' syndrome. Using highly advanced statistical analysis techniques such as factor analysis and machine learning, the study proposes a new definition of long-COVID, based on the association of symptoms and the impact on patients' quality of life 12 months after acute infection.


Long-COVID syndrome is a complex clinical condition whose pathogenetic mechanisms are not yet fully understood and which is estimated to affect 65 million patients worldwide. The definition used to date is that of the World Health Organisation, which is based on the new onset of symptoms approximately three months after an acute SARS-CoV-2 infection, which may be persistent, fluctuating or relapsing, and which cannot be explained by an alternative diagnosis. To date, more than 200 symptoms attributable to long COVID have been described, the most common of which are fatigue, muscle and joint pain, difficulty in concentrating, memory loss and respiratory disturbances, such as dyspnoea and persisting cough. The unspecific nature of long COVID symptoms and its clinical presentation limits the possibility to characterize it properly and to make a correct diagnosis. This aspect substantially undermines the opportunity to conduct clinical trials with the aim to improve the clinical management of patients with long COVID and foster the development of new drugs.

The Clinical Study

In the ORCHESTRA (Connecting European cohorts to increase common and effective response to SARS-CoV-2 pandemic) project, a multicentre prospective study was conducted from February 2020 to June 2022, in which SARS-CoV-2 patients, both outpatients and inpatients, were enrolled and followed up at 3-, 6- and 12-months post-acute infection through clinical and laboratory assessments. Clinical and biochemical features, antibody response, viral variants of interest, and the patients' physical and mental quality of life were assessed. The main objective was to identify risk and protective factors for the occurrence of long COVID syndrome based on patient characteristics and comorbidities, COVID disease severity, treatment and vaccination status.


The Results

The results of the study highlight new evidence that long COVID syndrome can be classified according to the combination of symptoms, with a different impact on physical and mental quality of life and different pathogenetic mechanisms, as demonstrated by the analysis of risk and protective factors associated with each clinical phenotype and severe long COVID syndrome.

These findings may contribute to the design of pathogenesis studies and the selection of high-risk patients for inclusion in clinical trials of new treatments of long COVID. Furthermore, they could support awareness campaigns and guide health policies for the control of COVID.

Specifically:

  • Of the 1796 patients enrolled, 1030 (57%) reported at least one symptom attributable to long COVID after 12 months

  • Cardiovascular disease (710, 40%) was the most frequently reported underlying clinical condition

  • The risk factors for the clinical pictures were different: women have a higher risk of chronic pain, chronic fatigue and neurological symptoms; patients with underlying chronic respiratory conditions (such as chronic obstructive pulmonary disease) have a higher risk of worsening of pre-existing respiratory symptoms; symptoms at the onset of COVID may be an early predictor of future long COVID: neurological symptoms increase not only the risk of neurosensorial impairment but also of respiratory and chronic fatigue clusters, while gastrointestinal symptoms during the acute infection are associated to chronic fatigue. e.

  • Female gender, gastrointestinal symptoms and kidney complications during acute infection increase the risk of severe long COVID syndrome

  • The most significant reduction in physical and mental quality of life was observed in patients with respiratory symptoms and chronic pain syndrome compared to negative controls (patients without long COVID)

  • Among the protective factors, having received steroid therapy during the acute phase of the disease would reduce the risk of persistence of neurosensory disorders such as taste and smell changes, while early treatment with monoclonal antibodies in patients with other comorbidities would reduce the risk of all long COVID clinical presentations.


The coordinator of the project Prof. Tacconelli highlights that the results allowed the identification of a severe long COVID at 12-months post-acute infection, which is characterised by the persistence of respiratory symptoms associated to chronic fatigue and pain. As demonstrated by validated questionnaires, the quality of life in patients with severe long COVID is seriously compromised. Women present, unfortunately, a 3-fold higher risk of developing severe long COVID compared to men. Vaccination reduces the probability to develop chronic fatigue and chronic pain clusters and severe long COVID.


The Rector of the University of Verona Prof. Pierfrancesco Nocini remarks that “the ORCHESTRA project shows how clinical research is essential to improve the diagnosis and treatment of patients with long COVID. The pandemic offered the opportunity to clearly demonstrate the central role of research and universities in case of a new disease under definition”.


Dr. Elisa Gentilotti, one of the lead authors of the study, concludes that 'early identification of patients at risk of developing severe long COVID can facilitate and support the development of new effective drugs'.




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. Find out more: https://www.id-care.net/projects/orchestra-

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