A blood test for the diagnosis of Long-COVID
New research identified proteins in the blood of Long-COVID patients that may lead to necessary diagnostic tests to set future therapeutic targets.
Signs of immune dysregulation in the blood
A team of researchers from the University of Zurich discovered alterations among proteins involved in the complement system in people with Long-COVID symptoms, but not in those who had improved after initial infection with COVID-19, or in those who had recovered from Long-COVID symptoms after 6 months. The team also found damage to red blood cells and platelets, as well as signs of damage to endothelial cells lining the blood vessels.
These biomarkers appeared after the researchers performed high-resolution analyses of more than 6,500 proteins found in the blood serum of 113 people infected with SARS-CoV-2, including 40 individuals who developed Long-COVID, and controls who had not been infected. The samples were taken for about a year, starting in 2020, by the team led by Carlo Cervia-Hasler from the University Hospital Zurich and the University of Zurich. The results were then validated by a larger cohort from Mount Sinai in New York.
Still limited information on Long-COVID
Not everyone recovers completely from COVID-19. About 20% of patients diagnosed with it and about 5% of all people infected with SARS-CoV-2 develop persistent symptoms, called Long-COVID, which can last for many months. Symptoms may include fatigue, post-exertional malaise (PEM) with cognitive impairment, and may involve multiple organs.
Although previous studies have shown that Long-COVID patients present signs of immune dysfunction, persistent immune cell activation and autoimmune antibody production, the main cause of Long-COVID is poorly understood. Even more, diagnostic biomarkers for this condition are not well defined. Currently, Long-COVID does not even have an effective treatment.
The analysis of blood samples from Long-COVID patients conducted in the study here mentioned revealed that alterations in serum proteins are the likely culprits of the condition. The results highlight potential biomarkers for the diagnosis of Long-COVID and could provide indications for the treatment of the condition.
Blood analysis to identify characteristics of Long-COVID
Carlo Cervia-Hasler and colleagues report the results of a longitudinal analysis of the serum of 113 patients who either recovered completely from COVID-19 or developed Long-COVID, as well as healthy controls. Using high-throughput proteomic approaches, the researchers measured serum levels of 6,596 human proteins among the study participants. Patients with confirmed acute COVID-19 were followed for up to one year and their blood serum was re-sampled at 6 months and, when possible, at 12 months.
Long-COVID patients showed changes in blood serum proteins, indicating dysregulated activation of the complement system, altered coagulation, and tissue lesions, suggesting ongoing thrombo-inflammatory responses. The authors show that, at the cellular level, the thrombo-inflammatory signature associated with Long-COVID was linked to an increase in monocyte-platelet aggregates. Dysregulation of complement proteins could contribute to the thrombo-inflammation associated with Long-COVID.
The study shows increases and decreases in the complement components of people with Long-COVID. According to the authors, these changes could be a clue as to why Long-COVID persists. Importantly, this result was replicated in an independent cohort in the United States.
Furthermore, research suggests that in individuals with Long-COVID, an increase in antibodies against other viruses (such as CMV and EBV) is evident and this could result in activation of the complement system that can lead to tissue damage. This finding further supports the idea that people with Long-COVID experience a condition of immune dysregulation, characterised by increased inflammation, altered autoantibody profiles and elevated antibody responses.
The researchers also found platelet dysregulation linked to Long-COVID, as already suggested by other research.
A diagnostic test based on blood examination
The researchers hope that these changes in complement activation can become a signature of Long-COVID in blood samples robust enough to develop a diagnostic test based on them.
Further and larger studies are needed to further investigate and confirm what has been discovered. In fact, this study is based on a relatively small number of patients and the cured cases (n=73) were young (median 36 years vs. 58 years), rarely had severe disease (16.4% vs. 62.5%) and rarely had been admitted to the ICU (4.1% vs. 30%) compared to the 6-month-old Long-COVID cases (n=40).
Furthermore, while providing new insights into complement protein alterations, it still does not explain the diversity of Long-COVID symptoms or their differential expression between individuals.
- Cervia-Hasler C, Brüningk SC, Hoch T, Fan B, Muzio G, Thompson RC, Ceglarek L, Meledin R, Westermann P, Emmenegger M, Taeschler P, Zurbuchen Y, Pons M, Menges D, Ballouz T, Cervia-Hasler S, Adamo S, Merad M, Charney AW, Puhan M, Brodin P, Nilsson J, Aguzzi A, Raeber ME, Messner CB, Beckmann ND, Borgwardt K, Boyman O. Persistent complement dysregulation with signs of thromboinflammation in active Long Covid. Science. 2024 Jan 19;383(6680):eadg7942. doi: 10.1126/science.adg7942. Epub 2024 Jan 19. PMID: 38236961.