Biomarker 1: Complement Proteins

A recent study titled "Persistent complement dysregulation with signs of thromboinflammation in active Long Covid," published in Science, conducted by Cervia-Hasler et al. from prestigious institutions in the U.S., Switzerland, and Sweden, examined 39 healthy individuals and 133 survivors of Covid-19. Of these survivors, 40 developed long-Covid within six months. Blood samples were collected during clinical evaluations, yielding a total of 268 samples for longitudinal analysis, with machine learning techniques applied to assess over 6,500 proteins.

The findings indicated that individuals who developed long-Covid exhibited heightened activation of the complement system during their Covid-19 infection, characterized by increased levels of C5bC, Factor Ba, and C2, while levels of C7 were reduced. This activation persisted even six months later. Conversely, in Covid-19 survivors who did not develop long-Covid, complement proteins returned to normal levels.

However, the data revealed significant overlap in C7 and C4bC levels among Covid-19 survivors who either did not develop long-Covid or who recovered from it, complicating the clinical interpretation of these biomarkers.

Consequently, although the results reached statistical significance, the clinical relevance of these findings remains limited. Thus, if a long-Covid patient has their C7 levels measured and no significant decrease is observed, it does not necessarily exclude a long-Covid diagnosis.

I will not delve into the intricacies of the complement system here; suffice it to say that it plays a crucial role in enhancing the immune response to eliminate foreign threats and cellular debris.

Biomarker 2: Thromboinflammation

The same study by Cervia-Hasler also identified increased levels of biomarkers indicative of tissue injury and thromboinflammation in long-Covid patients. Specifically, those with long-Covid had elevated blood levels of various proteins such as hemopexin, antithrombin III, and von Willebrand factor, among others.

However, similar to the complement proteins, there was considerable overlap in the levels of these thromboinflammation biomarkers between those with and without long-Covid, indicating that distinguishing between the two groups based solely on these markers is problematic.

In my own meta-analysis, I discovered similar trends regarding thromboinflammation biomarkers such as C-reactive protein (CRP) and D-dimer, which, while statistically significant, also exhibited substantial overlap between groups.

Biomarker 3: Cortisol

Another pivotal long-Covid biomarker study conducted by Klein et al. at Yale University and published in Nature in September 2023 found several immune system alterations in long-Covid participants. Notably, cortisol emerged as a key biomarker, showing significant statistical differences between groups. However, cortisol levels also largely overlapped between individuals with and without long-Covid.

Biomarker 4: Serotonin

The most compelling long-Covid biomarker identified in recent research is serotonin, highlighted in a groundbreaking study by Wong et al. from the University of Pennsylvania and the University of California. Their analysis of metabolic data revealed that serotonin levels were significantly reduced in both long-Covid patients and those with ongoing Covid-19.

The study also demonstrated that serotonin levels did not overlap significantly between Covid-19 survivors with and without long-Covid, indicating its potential as a distinct biomarker.

Wong et al. further explored the mechanisms behind serotonin reduction and its implications for long-Covid, linking it to unresolved viral inflammation and nutritional deficiencies affecting tryptophan absorption.

What It All Means

Among the various studies on long-Covid biomarkers published in prestigious journals, only the Cell study effectively illustrates how serotonin levels can differentiate between those with and without long-Covid. Other biomarkers, such as complement proteins and cortisol, show considerable overlap, diminishing their utility in clinical diagnosis.

It is often uncomfortable for researchers to acknowledge small effect sizes, as they undermine the perceived value of their work. This reluctance can skew public understanding, creating the illusion that a reliable diagnostic tool for long-Covid has been discovered.

Although serotonin shows promise as a viable biomarker, several challenges remain, including its potential association with other disorders and the lack of routine testing. Furthermore, variations in serotonin levels across long-Covid subtypes may complicate its diagnostic application.

In conclusion, while my perspective may evolve with ongoing research, the study by Wong et al. represents a significant step forward in understanding long-Covid biomarkers.

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