Blood test for long COVID: Could blood proteins predict risk?

• Researchers examined the link between blood protein levels and long COVID incidence.
• They found that levels of certain blood proteins six weeks after contracting SARS-CoV-2 may predict long COVID risk.
• They noted that larger studies are needed to confirm their results.

According to the World Health Organization (WHO), long COVID is characterized by symptoms that occur around three months after contracting SARS-CoV-2 that another diagnosis cannot explain.

Research suggests that while long COVID is more common among hospitalized patients, 36% of non-hospitalized patients without a clinically severe infection can develop the condition.

Another study suggests that up to 30% of the SARS-CoV-2 health burden may be due to long COVID and disability stemming from developing COVID-19.

Understanding how long COVID develops could help researchers and clinicians reduce the risk of developing the condition, and treat it more effectively.

Recently, researchers published their findings comparing blood samples from healthcare workers who had contracted SARS-CoV-2 and healthcare workers who had not.

They found that blood protein levels within six weeks of contracting SARS-CoV-2 could predict long COVID incidence.

“These changes in the blood that we observe shortly after infection indicate how the person’s immune system has handled the infection and may indicate a predisposition to developing persistent symptoms,” Dr. Wendy Heywood, senior research associate at University College London (UCL) Biological Mass Spectrometry Centre (BMSC), one of the study’s senior authors, told Medical News Today.

The study, led by University College London researchers, was published ineBioMedicine, a part of The Lancet Discovery Science.

20 proteins tied to long COVID

For the study, the researchers recruited 54 healthcare workers who had a PCR or antibody confirmed COVID-19 diagnosis, alongside 102 healthcare workers who did not have COVID-19.

All participants were recruited at the start of the pandemic in March 2020, and all cases of COVID-19 were classified as “non-severe.”

Participants underwent weekly evaluations via questionnaires and blood sample collections for up to 16 weeks. They then filled in symptom questionnaires 6 and 12 months after the start of the study.

After analyzing the data, the researchers found that those who tested positive for SARS-CoV-2 had increased levels of 12 proteins involved in oxidative stress, metabolic reprogramming, and cell adhesion—which facilitate cellular interaction—compared to those who tested negative.

They further found that the more protein levels were increased, the more they correlated with symptom severity.

The researchers also noted that abnormal levels of 20 proteins predicted the incidence of long COVID. Several of these proteins had anti-coagulant and anti-inflammatory effects.

Other predictive proteins included those involved in the production of red blood cells, and increased iron levels- previously linked to increased tissue damage through oxidative stress and impaired immunity.

The researchers concluded that non-severe SARS-CoV-2 disrupts proteins in the blood, and that blood protein levels may be able to predict long COVID risk.

Protein levels and inflammation

When asked how protein levels and long COVID may be linked, Dr. Dana Hawkinson, medical director of the Infection Control and Prevention program at The University of Kansas Medical Center, who was not involved in the study, told MNT:

“It still remains very unclear what, if any, influence the protein levels have. We do believe one of the major theories of long COVID has to do with persistent inflammation/inflammatory state, as mentioned in the authors’ discussion.”

“Some of these proteins identified certainly reflect an inflammatory state. This, in turn, could influence the symptoms of long COVID. [However], these proteins [may also be the] result of that inflammatory state, and not necessarily the cause.”
— Dr. Dana Hawkinson

Dr. Jimmy Johannes, pulmonologist and critical care medicine specialist at MemorialCare Long Beach Medical Center in Long Beach, CA, who was not involved in the study, also told MNT:

“While there is still a lot we don’t know about long COVID, there is suspicion that some of the symptoms may be related to small blood clots or dysregulation of inflammation.”

Study limitations 

When asked about the study’s limitations, Dr. Heywood pointed out a limited number of samples and cases from early in the pandemic.

“This study was performed with samples from one center. Further studies from other center cohorts should be done to confirm the findings. Also, these samples were collected during the first wave before the vaccine was available, which is useful to give us an insight [into] how long COVID may develop in unexposed people, but now, as most people are vaccinated or have had a COVID-19 infection, we need to see if these changes still occur,” she said.

Dr. Peter Robinson, professor of computational biology at The Jackson Laboratory in Farmington, CT, who was not involved in the study, told MNT:

“This is an interesting study, but its numbers are very small, there is a lack of proper independent validation, and the results are not compared against [protein levels] of other kinds of infection- which one would want to assess what is COVID-19 specific.”

“One of the problems in the field is that there are lots of relatively small studies that do not have the statistical rigor to be considered definitive and do not answer the question of what is really going on pathophysiologically,” he said.

“I do not mean to be overly critical of this paper, it is an interesting observation that hopefully will lead to more research, but I would not overemphasize its importance,” he explained.

What this means for treating long COVID

Dr. Heywood said it was early to talk about immediate applications.

“We cannot make something better until we can measure a biomarker as an outcome. Laboratory-based changes in biomarkers can be more reliable indicators of response to treatment than asking how a patient feels. This will be important in monitoring the success of any trials of new therapeutics,” she said.

“[B]eing able to identify people with a pre-disposition to developing long COVID early on could help us test new interventional treatments on the right people.”
— Dr. Wendy Heywood

Dr. Johannes said that while these findings are unlikely to affect the management of long COVID immediately, should they be replicated and validated in a larger study, they may lead to a test that can predict who is most likely to develop long COVID.

Dr. Hawkinson added that the results might one day be used to inform clinicians to prescribe medications, such as antiviral or anti-inflammatory agents, differently or earlier after COVID-19 diagnosis.

“For instance, maybe using Paxlovid early on for even young vaccinated patients may reduce risk of these persistent symptoms even though we have substantial data to support the fact that young, vaccinated patients do not have the significant benefit of hospitalization risk reduction that older patients have when using Paxlovid,” he said.

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