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Could Long Covid’s Signs of Immune Dysregulation in the Blood Help with Diagnostic Testing?


For an extended period, the elusive nature of long Covid has confounded scientists seeking its origins, complicating both diagnosis and treatment. The enigma surrounding its persistent symptoms and the challenge of definitively identifying affected individuals have spurred a quest for solutions. A ray of hope emerges from recent research published in Science, shedding light on proteins found in the blood of long Covid sufferers. These proteins may pave the way for a crucial diagnostic test and potential therapeutic targets.  


Researchers at the University of Zurich delved into the immune system, specifically the complement system, which plays a pivotal role in linking innate and adaptive responses. In individuals with lingering long Covid symptoms, disruptions in certain complement system proteins were identified, a phenomenon absent in those who recovered promptly post initial Covid-19 infection or after six months of battling long Covid. The study also pinpointed anomalies such as damaged red blood cells, platelets, and indications of harm to endothelial cells lining blood vessels.


The breakthrough findings stem from high-throughput analyses encompassing over 6,500 proteins in the blood serum of 113 Covid-infected individuals. This cohort included 40 individuals grappling with long Covid symptoms and controls uninfected by the virus. The research, led by Carlo Cervia-Hasler from University Hospital Zurich and the University of Zurich, initiated in 2020 and extended over a year. Subsequently, the results were validated using a larger dataset from Mount Sinai in New York.  


Cervia-Hasler expressed surprise at the pronounced disparities in complement proteins initially. However, the pieces of the puzzle began to align, as these anomalies resonated with various long Covid hypotheses, all converging towards the complement system. As the research progresses, understanding how these elements interconnect promises to unravel more about the intricate tapestry of long Covid.


Unraveling Long Covid: Exploring the Culprits Behind Persistent Symptoms

Numerous hypotheses surround the mysterious nature of long Covid, ranging from the presence of viral reservoirs retaining SARS-CoV-2, to persistent inflammation sparked by the initial infection, and the potential trigger of autoimmunity. Recent studies, including one in November 2023 published in Science Translational Medicine, have identified distinctive immune signatures in the blood of individuals grappling with long Covid.  


In the latest study published, researchers honed in on specific components of the complement system, noting fluctuations in people with long Covid. These changes could hold the key to understanding the lingering nature of the condition, according to Cervia-Hasler. The cascade of complement proteins responds initially to the virus, subsiding later and entering healthy cells. While the complement system is designed to combat infected and damaged cells, an overly active system may inadvertently harm healthy cells, perpetuating the battle. Cervia-Hasler highlighted the potential existence of a vicious cycle, questioning why the complement system remains active in long Covid. Could targeted complement therapy be the answer to break this cycle?


Nadia Roan, a senior investigator at the Gladstone Institute and a professor at the University of California, San Francisco, not affiliated with the study, expressed fascination with the findings. In an interview, she characterized the observed dysregulation as complex, with some complement components rising while others decline. Overall, the results suggest abnormal complement pathways in individuals with long Covid. Roan, who authored a Nature Immunology paper in January on immune responses in long Covid, found it intriguing that complement dysregulation appears to normalize in those who subsequently recover from the condition.  


Unveiling Immune Complexity: Clues in Protein Analysis for Long Covid Diagnosis 

The University of Zurich's meticulous protein analysis has unveiled a noteworthy phenomenon, echoing observations made by other researchers: reactivation of antibodies against past herpesvirus infections. This discovery provides further backing to the notion that individuals enduring long Covid grapple with immune dysregulation, marked by heightened inflammation, altered autoantibody profiles, and increased herpesvirus antibody responses, as noted by Roan.  


Cervia-Hasler envisions these shifts in complement activation as potential signatures of long Covid in blood samples, paving the way for a diagnostic breakthrough. Such a test would not only assess complement activation but also consider age, body mass index, and indicators of abnormal blood clotting coupled with inflammation. The primary objective is to provide tangible evidence for patients who often face the stigma of being labeled as psychiatric cases or receive misguided treatment due to the subjective nature of their reported symptoms. Cervia-Hasler emphasizes the urgency, especially in an environment where Covid tests are on the decline, making accurate diagnoses even more challenging.


Navigating the Future: Unraveling Long Covid's Path Forward

Looking ahead, Cervia-Hasler emphasizes the need for more extensive and rigorous trials to delve deeper into their findings. The focus is on extended observation periods post-initial Covid-19 infection, aiming to comprehend how the dynamics may evolve over time. Acknowledging the diversity among Covid patients, he underscores the importance of nuanced investigations to tailor understanding to individual cases.  


Maintaining a cautious stance, Roan from Gladstone Institute stresses the pivotal role of determining whether dysregulated complement is a true cause of long Covid, a potential therapeutic target. However, she also highlights the necessity for larger cohorts to validate the utility of complement dysregulation as a biomarker, considering the varied nature of the condition.


Wolfram Ruf, from Johannes Gutenberg University in Mainz, Germany, leans towards the prospect of a diagnostic tool rather than an immediate treatment. While acknowledging mixed results from therapeutic interventions in acute Covid-19, Ruf sees potential for clinical testing based on the specific pathological features associated with long Covid.  


Cervia-Hasler expresses hope that other research groups will explore overlooked pathways, fostering a collaborative effort towards diagnostic tools or therapeutic solutions. The collective goal is to steer the field towards tangible outcomes that can aid in early diagnosis and effective interventions for long Covid, offering hope to those grappling with this perplexing condition.

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