‘Early events’ can increase a person’s risk for long COVID
Key takeaways:
- A higher viral load and delayed SARS-CoV-2 clearance can increase the risk for long COVID.
- Study participants who experienced viral rebound had a 13-fold higher risk for long COVID than those who did not.
SAN FRANCISCO — A slow immune response to SARS-CoV-2 infection, delayed viral clearance, and viral rebound can all increase a person’s risk for long COVID, according to study data.
“A theme that seems to be emerging in the long COVID field is that early events matter for long COVID risk,” Annukka Antar, MD, PhD, assistant professor of medicine at the Johns Hopkins University School of Medicine, said during a presentation at the Conference on Retroviruses and Opportunistic Infections.
According to Antar, studies in the last 2 years have suggested that early mucosal virus host kinetics, delayed clearance of viral RNA from the upper respiratory tract and higher titers of infectious virus during acute infection are associated with long COVID risk.
Infections lasting longer than 28 days have been found to increase certain symptoms of long COVID, she also noted.
“Overall, there’s an emerging theme that if you have slower immune responses at the mucosal surface and longer delayed clearance of the virus during acute infection, you’re more likely to get long COVID,” she said.
With interest in how the early kinetics of SARS-CoV-2 affects the potential development of long COVID, Antar said, “We wanted to ask, Is viral rebound during acute infection associated with long COVID?”
Antar and colleagues analyzed data collected between October 2021 and February 2022 from 7,361 people who enrolled in the NIH’s Rapid Acceleration of Diagnostics (RADx) initiative to speed development of COVID-19 self-tests.
The participants, who did not have COVID-19 or any COVID-19 symptoms, self-collected nasal specimens for SARS-CoV-2 testing every 24 or 48 hours for 10 or 14 days in one of two separate studies in the initiative, Antar said.
Antar and colleagues identified roughly 450 participants who tested positive for SARS-CoV-2 during the two RADx studies, sending them a survey asking if participant had long COVID, whether they had symptoms lasting 3 months or longer that they had not had before COVID-19 and what symptoms they had during long COVID.
The researchers received a total of 244 survey responses, 215 of which were assessed in a viral rebound analysis and 172 that were “intelligible” enough to create a slope of model clearance for the participant.
Of the 172 responses that researchers were able to create a slope of clearance for, 34% had ever had long COVID. According to the researchers, participants who had long COVID took more than 1 day longer to clear the virus after peak viral load compared with those who never developed long COVID (10 days; 95% CI, 9.25-10.8 vs. 8.7 days; 95% CI, 8.28-9.01).
Fatigue, brain fog, shortness of breath and gastrointestinal symptoms were the post-acute symptoms most significantly associated with longer viral clearance slopes, they reported.
Among the 215 surveys assessed for viral rebound, 36% had ever had long COVID and 35% experienced viral rebound, which researchers said translated to a 13-fold higher risk for long COVID if a participant had a rebound at the time of acute infection (OR = 13.1; 95% CI, 6.79-26.2).
“To sum up, we found that slower viral clearance during acute infection is associated with subsequent long COVID, and is stronger in people with more long COVID symptoms,” Antar said. “This is especially true in women, but not men, and it is strongest with certain long COVID symptoms ... [as is] experiencing viral rebound during acute infection.”
References:
- Herbert C, et al. Abstract 935. Presented at: Conference on Retroviruses and Opportunistic Infections; March 9-12, 2025; San Francisco.
- NIH. Rapid acceleration of diagnostics (RADx). https://www.nih.gov/research-training/medical-research-initiatives/radx. Accessed March 20, 2025.
Perspective
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This is an interesting analysis showing that delayed viral clearance and viral rebound are associated with increased odds of developing long COVID. This is important because it lends support to the hypothesis that long COVID may be driven in some individual ways by viral persistence.
Delayed viral clearance, and more rebound, could translate into more opportunities for the virus to find hospitable or immune-privileged tissue sites to hide and, hence, a higher chance of viral persistence. Alternately, individuals who experience delayed viral clearance and more rebound may have immune characteristics that may predispose them to a higher risk for long COVID.
These explanations need to be empirically evaluated. Nevertheless, these new results are exciting. They may help unlock a greater understanding of the underlying mechanisms of long COVID and may have implications for prevention and treatment.
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Herbert C, et al. Abstract 935. Presented at: Conference on Retroviruses and Opportunistic Infections; March 9-12, 2025; San Francisco.
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