Long COVID, or post-acute sequelae of SARS-CoV-2 (PASC), represents a significant and lingering burden on individuals who have recovered from the acute phase of COVID-19. This syndrome manifests itself in patients as a constellation of symptoms that persist well beyond the expected recovery period for the initial viral infection. Specifically, individuals suffering from Long COVID experience symptoms that continue for at least 60 days post-infection and may extend for at least 90 days. The range of symptoms associated with PASC is extensive and heterogeneous, with effects that can significantly impede activities of daily living and impact almost every major organ system. The persistence and severity of these symptoms can vary greatly from one person to another, leading to weeks or even months of ongoing health issues.
The challenges of Long COVID are compounded by the difficulty in establishing a unanimous clinical diagnosis due to the highly variable impact the condition has on different individuals. This variability not only affects the individuals' quality of life but also hampers the effectiveness of treatment efforts, as there is no one-size-fits-all solution. The underlying immune response, especially the inflammatory processes that occur post-infection, is crucial in determining the trajectory of recovery or further deterioration of health in these patients. An overactive or dysregulated immune response, particularly a sustained inflammatory state, has been consistently linked with unfavorable disease prognoses and can have serious long-term health consequences.
In a concerted effort to unravel the complexities of Long COVID, we at the Allen Institute For Immunology along with Dr. Julie McElrath, M.D., Ph.D., Senior Vice President, and Director of Fred Hutch's Vaccine and Infectious Disease Division, and Julie Czartoski, ARNP, Research Clinician, analyzed proteins circulating in the bloodstream. We discovered a unique set of inflammation-associated molecules that were present exclusively in a subset of Long COVID patients. This inflammatory signature was not detected in individuals who had fully recovered from COVID-19. Our study comprised 55 Long COVID patients, and strikingly, about two-thirds of this group exhibited persistently high levels of inflammatory markers. To provide a comparative perspective, we also evaluated blood samples from 25 individuals who had recovered from COVID-19 and 25 volunteers who were negative for COVID-19 infection. The latter two groups did not exhibit the inflammatory markers seen in the Long COVID cohort, suggesting a distinct pathophysiological process in those with prolonged symptoms.
Our work has illuminated a critical aspect of Long COVID: the persistence of inflammation, which is atypical for the normal resolution of an immune response following infection. A noteworthy finding from the study is the elevated level of specifically interferon-gamma (IFN-γ), a protein that plays a pivotal role in inflammation and immune response, which lingered in the blood of a subset of patients beyond 60 days post-infection onset.
Notably, our study identified a correlation between higher body mass index (BMI), older age and the predisposition to PASC with elevated levels of IFN-γ. This association is concerning given that high levels of IFN-γ have been implicated in poor outcomes across a spectrum of diseases and may predispose individuals to the development of autoimmune conditions. These insights suggest that the inflammatory serum protein signature found in Long COVID patients could potentially serve as a biomarker to stratify patients in clinical trials. Such stratification could enable the identification of those who might derive the greatest benefit from immunomodulatory treatments, thereby enhancing patient outcomes and advancing our understanding of the disease.
The connection between inflammation and Long COVID had been suggested by previous studies, but this research marks the first time that the persistence of these inflammatory markers has been tracked over time in the same set of patients. The implications of these findings are significant. They suggest that certain types of anti-inflammatory drugs could alleviate symptoms in some Long COVID patients. However, there is a clear need for precision medicine – tailored treatments based on individual characteristics and disease manifestations – to effectively address the complexities of Long COVID.
We have characterized the type of inflammation found in this subset of Long COVID patients as "inflammatory Long COVID," similar to the inflammation observed in autoimmune diseases such as rheumatoid arthritis, systemic Lupus, Inflammatory Bowel Disease or Chron’s disease. In diseases like rheumatoid arthritis, targeted treatments, including a class of drugs known as JAK inhibitors, have been successful. The parallels drawn here raise the possibility that JAK inhibitors might also prove beneficial for Long COVID, although they have not yet been tested for this indication.
This study raises the "big question" for clinicians and researchers alike: Can we differentiate between Long COVID patients with persistent inflammation and those without? The answer to this question is crucial for planning clinical trials and for clinicians to determine targeted treatments for their patients. The ability to identify these inflammatory markers in patients could lead to a better understanding of Long COVID and its management. If these markers can guide the use of specific treatments, then it opens a path to potentially effective therapies for those suffering from Long COVID.
The study's findings also emphasize the need for further research into the mechanisms underlying Long COVID and the development of diagnostic criteria that can account for its heterogeneous nature. By understanding the immunological underpinnings of this condition, researchers and clinicians can work towards the development of more effective therapeutic interventions. Moreover, the recognition of the inflammatory nature of Long COVID underscores the importance of considering the immune system's role in the pathogenesis and persistence of symptoms, thereby offering a new lens through which to view and treat this condition.
As the scientific community continues to investigate Long COVID, this research serves as a foundation for future studies and a beacon for patient care strategies. The potential for using existing drugs to treat new manifestations of disease exemplifies the agility required in medical research and patient care, particularly in the face of emerging diseases and syndromes. The efforts to identify biomarkers for Long COVID and to explore existing therapeutics for new applications are critical steps in addressing the ongoing challenges posed by this condition.