The researchers concluded that even after two years, many patients with post-COVID-19 syndrome had not recovered, and the most common symptoms continued to be fatigue, exercise intolerance and cognitive difficulties. This indicates that the approach to post-COVID-19 syndrome should be multidisciplinary, considering not only the physical but also the social and psychological aspects involved in the recovery of patients.
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has infected more than 750 million people worldwide. In addition to the immediate health problems caused by the infection, many people have reported persistent symptoms that have continued for months after the acute phase of the disease.
The World Health Organization (WHO) has defined this condition, called post-COVID-19 syndrome (PCS), as the presence of symptoms that last for at least two months after the initial infection, with no alternative medical explanation. The term "long COVID" has also been widely used to refer to this condition.
However, estimates of the prevalence of post-COVID-19 syndrome vary widely across studies, in part because diagnostic criteria are not always the same and because many early studies focused only on hospitalized patients, excluding most people who had mild or moderate illness and did not require hospitalization.
Furthermore, many studies on post-COVID-19 syndrome have faced methodological difficulties, such as the lack of a control group of people who had never had COVID-19, which made it difficult to distinguish between symptoms that were actually caused by the virus and those that may have other origins.
To better assess post-COVID-19 syndrome, researchers used questionnaires in which participants reported their own symptoms and limitations in daily life.
Although these symptoms have an impact on quality of life and work capacity, they are not specific to post-COVID-19 syndrome alone and can also occur in other medical conditions. In addition, many of the symptoms reported cannot be directly measured in laboratory or imaging tests, making it more difficult to establish a definitive diagnosis.
More recent studies, however, have been able to detect neurocognitive changes in patients with post-COVID-19 syndrome, which suggests that the condition may affect brain function. The results of cardiac and pulmonary tests have been inconsistent, with some studies indicating problems in these areas and others finding no significant changes.
Laboratory tests of patients with post-COVID-19 syndrome have shown changes in some blood biomarkers, such as different levels of cytokines (molecules involved in the inflammatory response) and cortisol (a hormone linked to stress). However, these studies were often small and did not include adequate comparison groups, making the results difficult to interpret.
Furthermore, some of these changes may be more closely linked to factors such as obesity and age than to post-COVID-19 syndrome. Obesity, for example, was already known as a risk factor for cognitive and inflammatory problems even before the pandemic and, in fact, has been linked to post-COVID-19 syndrome.
In studies on inflammation, body mass index (BMI) and gender have also emerged as factors that could confound the results, making it more difficult to understand the true impact of post-COVID-19 syndrome.
Researchers conducted a study in Germany to better understand post-COVID-19 syndrome and identify possible risk factors for its persistence. The study involved 1,558 people between the ages of 18 and 65, of whom 982 had post-COVID-19 syndrome and 576 served as a control group, as they had fully recovered from COVID-19.
These individuals were followed over time and underwent medical tests, including neurocognitive, cardiopulmonary and laboratory tests.
About 68% of patients with post-COVID-19 syndrome continued to have symptoms more than a year after the initial infection, while 78.5% of the control group remained free of COVID-19-related health problems.
The researchers noted that some characteristics were associated with a more difficult recovery: people with more severe infection, without a steady job before COVID-19 or with a lower level of education were more likely to continue to have post-COVID-19 syndrome.
On the other hand, those who recovered better tended to have mild infection, worked full-time before the illness and did not require specialized follow-up or post-COVID rehabilitation.
Another important finding was that the most common symptoms of post-COVID-19 syndrome were intense fatigue, cognitive difficulties, shortness of breath and psychological problems, such as anxiety and depression.
Additionally, 35.6% of patients with persistent post-COVID-19 syndrome reported extreme exertional malaise (PEM), a hallmark symptom of chronic fatigue syndrome (ME/CFS).
For these patients, symptoms were even more severe and included more pain and poorer performance on tests of physical and cognitive function.
Medical examinations showed some objective differences between patients with post-COVID-19 syndrome and those who fully recovered.
For example, patients with post-COVID-19 syndrome had reduced handgrip strength, lower maximal oxygen consumption (an indicator of physical endurance), and worse respiratory efficiency during exercise, suggesting some limitation in exercise capacity.
However, no significant differences were found in cardiac or laboratory tests. Tests to detect the persistent presence of the SARS-CoV-2 virus in the body were negative, indicating that post-COVID-19 syndrome does not appear to be related to ongoing replication of the virus.
In addition, there was no evidence of reactivation of the Epstein-Barr virus (EBV), which has been suggested as a possible cause of post-COVID-19 syndrome in some studies.
Other laboratory tests, including tests for inflammation, coagulation, and hormones, also showed no significant changes that could explain the symptoms.
They concluded that even after two years, many patients with post-COVID-19 syndrome had not yet recovered, and the most common symptoms continued to be fatigue, exercise intolerance and cognitive difficulties.
Despite this, no clear biological cause was identified for most symptoms in laboratory and imaging studies. This suggests that post-COVID-19 syndrome may be influenced by a combination of factors, including individual predisposition, dysregulated immune response, and psychosocial aspects.
In addition, variables such as educational level, work history, and access to medical care appear to play a role in both the development and recovery from post-COVID-19 syndrome.
These findings reinforce the need for further research to better understand the mechanisms underlying post-COVID-19 syndrome and develop effective treatment strategies. Furthermore, the researchers point out that a history of post-exertional malaise (PEM) may be an important indicator to identify the most severe cases of the syndrome and help personalize care for these patients.
As limitations of the study, the authors mention that they did not have information about the patients' condition before infection, which makes it difficult to assess whether some symptoms were already present before COVID-19.
People in serious condition or with difficulty attending appointments were also not included, which may have affected the results.
Overall, this study expands knowledge about long COVID and shows that, although many symptoms persist for years, there is still little evidence of significant organic damage detectable in clinical and laboratory tests.
This indicates that the approach to post-COVID-19 syndrome should be multidisciplinary, considering not only the physical aspects, but also the social and psychological aspects involved in the patients' recovery.
READ MORE:
Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 syndrome in the second year after acute infection: A population-based, nested case-control study
Raphael S. Peter, Alexandra Nieters, Siri Göpel, Uta Merle, Jürgen M. Steinacker, Peter Deibert, Birgit Friedmann-Bette, Andreas Nieß, Barbara Müller, Claudia Schilling, Gunnar Erz, Roland Giesen, Veronika Götz, Karsten Keller, Philipp Maier, Lynn Matits, Sylvia Parthé, Martin Rehm, Jana Schellenberg, Ulrike Schempf, Mengyu Zhu, Hans-Georg Kräusslich, Dietrich Rothenbacher, Winfried V. Kern, on behalf of the EPILOC Phase 2 Study Group
PLoS Med. 2025 Jan 23 ; 22 (1) : e1004511
Abstract:
Self-reported health problems following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are common and often include relatively non-specific complaints such as fatigue, exertional dyspnoea, concentration or memory disturbance and sleep problems. The long-term prognosis of such post-acute sequelae of COVID-19/post-COVID-19 syndrome (PCS) is unknown, and data finding and correlating organ dysfunction and pathology with self-reported symptoms in patients with non-recovery from PCS is scarce. We wanted to describe clinical characteristics and diagnostic findings among patients with PCS persisting for >1 year and assessed risk factors for PCS persistence versus improvement.
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