Researchers studying proteins found in the complement system, an important part of the immune system, of Long-COVID patients have discovered a blood protein "signature" that may improve diagnosis and lead to treatments for the debilitating disease.

About 5% of people infected with SARS-CoV-2 do not recover from acute illness and instead develop debilitating, long-term symptoms that are often referred to as "Long-COVID." Although the cause is unknown, current hypotheses include tissue damage, viral reservoirs, autoimmunity, and ongoing inflammation. There are currently no diagnostic tests or treatment options for this condition.

Using proteomics, the large-scale study of proteins, researchers at the University of Zurich and University Hospital Zurich have discovered a pattern in the blood proteins of Long-COVID patients and the effect these proteins have on a part of the immune system called the complement system.

The complement system is part of the innate immune system and consists of different proteins in the plasma and on cell surfaces that react with each other to enhance the ability of antibodies and phagocytes to clear microorganisms and damaged cells, promote inflammation, and attack pathogens.

Researchers followed 113 COVID-19 patients for a year, 33% of whom had severe disease according to World Health Organization (WHO) criteria. After 6 months, 40 of the 113 patients had a longer course of disease. At 12 months of follow-up, 22 of 40 Long-COVID patients reported persistent symptoms and 10 had recovered (8 were lost to follow-up).

To identify biomarkers of Long-COVID, the researchers collected serum from healthy controls and COVID-19 patients during acute viral infection and 6-month follow-up and measured 6,596 different serum proteins using two high-throughput proteomic methods. The researchers observed differences in serum protein levels between patients with severe COVID-19 and patients with mild acute COVID-19, as well as differences in serum protein levels between patients with Long-COVID and those without Long-COVID during the acute phase of infection and six-month follow-up.

"The analysis of which proteins are altered in Long-COVID confirmed an overactivity of the complement system," said Carlo Cervia-Hasler, first author of the study. "Patients with active Long-COVID also have elevated blood levels, indicating damage to various body cells including red blood cells, platelets, and blood vessels."

The researchers say the changes observed in Long-COVID patients suggest interactions between complement proteins, which are involved in blood clotting and repair of tissue damage and inflammation. They noted that blood levels in Long-COVID patients returned to normal within six months, suggesting that active Long-COVID is characterized by the serum protein patterns seen in the study.

OnurBoyman, the study's corresponding author, said: "In Long-COVID patients, the complement system no longer returns to its basal state but remains activated, thereby also damaging healthy cells."

The findings of this study caused quite a stir in the medical community.

Jeremy Nicholson, Professor of Medicine at Murdoch University in Western Australia and Director of the Australian National Phenotyping Centre, said: "This paper helps identify some of the fundamental immunological perturbations that help us understand thromboembolic inflammatory effects - such as those affecting the lining of blood vessels - that may cause A more general systemic problem (all organs have blood vessels). This paper sheds new light on complement protein perturbations, but still cannot explain the diversity of long-term symptoms of COVID or the differential expression among individuals. The fact that this work is based on proteomic data from a relatively small number of patients is unlikely to explain everything."

Because the biomarkers the researchers discovered were limited to Long-COVID patients, were diagnostically accurate six months after symptom onset, and were not affected by any COVID-19 medical history information, the researchers say they have clinical applicability. Existing therapies targeting complement pathways affected by Long-COVID could provide new treatment strategies for the disease.

The study was published in the journal Science.