Other significant early predictors of prolonged COVID symptoms – which the researchers called postacute sequelae – were having type 2 diabetes, SARS-CoV-2 RNAemia, and Epstein-Barr virus (EBV) viremia, Yapeng Su, PhD, of the Institute for Systems Biology (ISB) in Seattle, and colleagues wrote in Cell.
Having EBV viremia suggested that latent EBV has been reactivated, the authors noted.
Dr. James R. Heath
“The most important postacute sequelae [that is conditions that are consequences of a disease] of COVID is the presence of autoantibodies,” James R. Heath, PhD, president of ISB and a bioengineering professor at the University of Washington, Seattle, said in an interview. “It’s about two times more important than the others.”
Dr. Heath and coauthors said early detection of this and other variables could prompt earlier aggressive treatment in patients susceptible to long COVID and ward off lingering symptoms.
“These predictive measures of long COVID can also help to better inform patients of their possible disease course,” study coauthor Daniel G. Chen, an undergraduate researcher at ISB, said in an interview. “We were also able to partially resolve the immunological underpinnings of some postacute sequelae of COVID in a way that suggested potential therapies, and the timing of those therapies.”
Mr. Daniel G. Chen
For example, he continued, the use of antivirals very early in the infectious course may mitigate the later development of long COVID. “This will, of course, have to be explored in an appropriately designed clinical trial.
“We also identified biomarkers of certain types of long COVID, such as neurological sequelae. Those biomarkers can help define the condition, which is a first step towards developing treatments.”
Study findings
With COVID patients monitored for 2 or 3 months, the study findings of the international “multiomic profiling” analysis include:
- Subclinical patient autoantibodies that reduce anti–SARS-CoV-2 antibodies suggest there is immune dysregulation during COVID-19 infection.
- Reactivation of latent other viruses during initial infection may be contributing to long COVID.
- Gastrointestinal postacute sequelae of COVID presents with a unique postacute expansion of cytotoxic T cells.
- SARS-CoV-2–specific and cytomegalovirus-specific CD8+ T cells displayed unique dynamics during recovery from infection.
According to the authors, as many as 69% of COVID-19 patients suffer from long COVID – a range of new, recurrent, or ongoing problems 4 or more weeks following initial SARS-CoV-2 infection. These may include memory loss, gastrointestinal distress, fatigue, anosmia, and shortness of breath.
Long COVID has been associated with acute disease severity, and is suspected to be related to autoimmune factors and unresolved viral fragments, according to the paper.
Research methods
The international study did a deep and detailed dive into multiple molecular markers of long COVID. It enrolled 209 COVID-19 patients with varying degrees of disease severity and matched them to 457 healthy controls. The researchers’ goal was to identify discrete and quantifiable long COVID factors and guide possible preemptive treatment.
Patients were assessed at three time points: at initial diagnosis, during the acute disease phase about a week later, and again 2 to 3 months post onset of symptoms after recovery from the acute phase of COVID. At the third assessment, some patients had lingering symptoms such as fatigue (52% ), cough (25%), and loss of taste or sense of smell (18%).
Blood draws were analyzed for autoantibodies and SARS-CoV-2–specific antibodies, global plasma proteomic and metabolomic profiles, and single-cell multiomic characterizations of peripheral blood mononuclear cells.
Each blood draw was paired with nasal-swab and plasma measurements of SARS-CoV-2 viral load and the data sets were integrated with electronic health records and self-reported patient symptoms to guide the interpretation of the molecular signatures of long COVID.
Author conclusions
The authors found an association between T2 hyperinflammation and long COVID–anticipating autoantibodies. This association further implies that hyperinflammation-controlling therapies in the acute stage of COVID may influence whether a patient experiences long COVID. “However, the detailed timing and context of these therapies matter, and, thus, future well-controlled studies will be needed to test these and other therapeutic implications,” Dr. Su and colleagues wrote.
Moreover, the negative correlations between anti–SARS-CoV-2 IgG and certain autoantibodies may suggest that patients with elevated autoantibody levels are more susceptible to breakthrough infections, the authors said.
“Many patients with high autoantibodies simultaneously have low protective antibodies that neutralize SARS-CoV-2, and that’s going to make them more susceptible to breakthrough infections,” Mr. Chen explained.*
“Detectability of most [long COVID-19 factors] at COVID diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests [long COVID] treatment strategies,” they wrote.
According to Mr. Chen, there are clear similarities in underlying immunobiology between patients with COVID autoantibodies and patients with systemic lupus erythematosus.
“These findings are also helping us frame our thinking around other chronic autoimmune conditions, such as postacute Lyme syndrome, for example,” said Dr. Heath.
The bottom line, said Mr. Chen, is that measuring early long COVID indicators may result in preventive treatments. “An example is the cortisol deficiency we see in certain long COVID patients. There are known treatments such as cortisol replacement therapy that should be explored for this group.”
Outside expert’s take on findings
Commenting on the study, Sherry Hsiang-Yi Chou, MD, who was not involved in the research, called the study a very important first step in understanding the path of this complex phenomenon and perhaps other conditions with long-term side effects.
Dr. Sherry Hsiang-Yi Chou
“The researchers have done huge amount of innovative scientific work. They’ve shown the DNA signature of how our bodies respond to this disease,” said Dr. Chou, who is chief of the division of neurocritical care at Northwestern Medicine in Chicago.
“This type of research will help us scientifically understand and differentiate the various syndromes within long COVID. It will help identify who’s at risk for different aspects of this syndrome and lead to following them for longer periods in clinical trials,” she added.
The authors acknowledged that lengthier studies in larger cohorts were needed to see which patients will develop long-term chronic postacute sequelae of COVID.
This research was supported by the Wilke Family Foundation, the Parker Institute for Cancer Immunotherapy, Merck, and the Biomedical Advanced Research and Development Authority. Other support came from the National Institutes of Health, the Bill and Melinda Gates Foundation, Saint John’s Cancer Center, Fred Hutchinson Cancer Research Center, and the European Union’s Horizon 2020 research and innovation program. Dr. Heath is a cofounder of Pact Pharma. He and several coauthors disclosed various ties to multiple private-sector companies. Mr. Chen and Dr. Chou had no competing interests.
*Correction, 1/28: An earlier version of this story misidentified Daniel G. Chen, an undergraduate researcher at ISB.