Newswise — An excessive inflammatory reaction may underlie numerous long COVID instances, as per a recent investigation conducted by the Allen Institute and Fred Hutchinson Cancer Center.

Analyzing circulating blood proteins, the researchers discovered a cluster of inflammatory-related molecules exclusively found in a portion of long COVID patients, absent in individuals who had recovered from the illness. The team published their findings in today's issue of the journal Nature Communications.

Among the 55 long COVID patients, approximately two-thirds exhibited consistently elevated levels of specific inflammation markers. The researchers further examined blood samples from 25 individuals who had recovered from COVID-19 and 25 volunteers who had never contracted the disease (to the best of their knowledge). The absence of inflammatory indications in the blood of those without long COVID was evident.

The volunteer patients included in this recent analysis are participants in the Seattle COVID Cohort Study, a larger, ongoing research initiative conducted at Fred Hutch. The study is overseen by Julie McElrath, M.D., Ph.D., Senior Vice President and Director of Fred Hutch's Vaccine and Infectious Disease Division, along with Julie Czartoski, ARNP, who serves as a Research Clinician at the Hutch.

While prior studies have observed connections between inflammation and long COVID, the recent study is notable for being the first to track the endurance of these inflammatory markers over time within the same group of patients.

Troy Torgerson, M.D., Ph.D., the Director of Experimental Immunology at the Allen Institute for Immunology, which is a division of the Allen Institute, highlighted the significant implication of these findings. He suggested that specific types of anti-inflammatory medications could potentially alleviate symptoms in certain long COVID patients. However, physicians lack a means of determining which treatments would be beneficial for individual long COVID patients. This highlights the need for precision medicine approaches in addressing a disease that continues to pose challenges due to its enigmatic nature.

Torgerson, who co-led the Nature Communications publication alongside McElrath, Aarthi Talla, Senior Bioinformatician at the Allen Institute for Immunology, Suhas Vasaikar, Ph.D., former Senior Bioinformatics Scientist (now a Principal Scientist at Seagen), and Tom Bumol, Ph.D., former Executive Vice President and Director, emphasized the crucial question of identifying long COVID patients with persistent inflammation. This distinction would be valuable for planning clinical trials and assisting clinicians in determining targeted treatments for their patients.

The blood markers identified in this group of patients with "inflammatory long COVID," as referred to by the scientists, indicate a type of inflammation akin to that observed in autoimmune conditions such as rheumatoid arthritis. Interestingly, JAK inhibitors, a class of drugs already used for treating rheumatoid arthritis, have the potential to address this type of inflammation. However, their efficacy in treating long COVID has not been tested yet.

Additionally, the researchers aim to refine the molecular signature of "inflammatory long COVID" by identifying a select few markers that can be utilized in clinical settings to distinguish this specific subset of long COVID patients from others. This would contribute to better patient stratification and personalized treatment approaches.

Refining treatment options

The Seattle COVID Cohort Study, spearheaded by Fred Hutch, was initiated in the early months of 2020, shortly after the COVID-19 pandemic led to the closure of businesses and schools across the United States. Initially, the study's purpose was to monitor the immune responses of individuals with mild or moderate COVID-19 over an extended duration. The objective was to examine the intricacies of a "successful" immune response, characterized by minimal illness severity, no hospitalization requirements, and complete recovery.

However, during their initial research in 2020, while studying the immune responses of 18 COVID-19 patients, the team discovered an intriguing observation. They observed that a few individuals, despite not experiencing severe illness, did not fully recover from their symptoms. These cases represented early instances of what would later be referred to as long-haul COVID or long COVID. This realization prompted the researchers to delve further into understanding the complexities and implications of this phenomenon.

During the initial stages of the study, the scientists observed a notable pattern among the patients with long COVID. Specifically, they noticed that a particular immune response, namely inflammation, remained consistently elevated in these individuals. In contrast, patients who fell ill but eventually fully recovered exhibited a temporary increase in inflammation levels as their bodies fought off the infection, which subsequently returned to normal as they regained their health. However, in long COVID patients, the inflammation levels remained persistently high and did not return to baseline. This observation highlighted the distinct and ongoing immune dysregulation experienced by individuals with long COVID.

Recognizing the importance of investigating a larger cohort of long COVID patients, the research team made the decision to expand their study. Their focus shifted towards analyzing a panel of 1500 proteins present in the blood. Through this comprehensive assessment, the team identified distinct molecular categories or "buckets" of long COVID, specifically inflammatory and non-inflammatory long COVID. By gaining a deeper understanding of the molecular foundations and subsets of the disease, the researchers emphasized that this knowledge would significantly contribute to guiding the design of clinical trials and making informed decisions regarding treatment strategies for long COVID patients.

Talla highlighted that the primary objective is to provide effective treatments for long COVID patients. While the term "long COVID" is commonly used, the findings from this study indicate that a one-size-fits-all approach may not be suitable for all patients. Talla emphasized the importance of recognizing the heterogeneity within the long COVID population and tailoring therapies accordingly. Individualizing treatment approaches based on specific subsets or categories identified through molecular analysis can lead to more targeted and successful interventions.

According to Torgerson, individuals with non-inflammatory long COVID may potentially experience permanent organ or tissue damage resulting from the disease. Consequently, their treatment requirements would significantly differ from those with high levels of inflammation. Importantly, the scientists noted that distinguishing between these groups based solely on symptoms is not possible. Therefore, if anti-inflammatory drugs prove effective in addressing inflammatory long COVID, it would be essential to screen patients to accurately determine which form of long COVID they have. This screening process would facilitate the appropriate selection of treatments based on individual patient profiles.

“We hope these findings provide features of long COVID that may guide potential future therapeutic approaches,” McElrath said.