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Pre-infection symptoms and functional status associated with long COVID risk in 65,464 U.S. adultsDid you know older age and female sex increase long COVID risk?

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Key Takeaway
Note that pre-infection symptoms and functional status are associated with long COVID risk in this large cohort study.

This retrospective cohort study evaluated 65,464 U.S. adults with a history of COVID-19 enrolled in the All of Us Research Program. The analysis assessed the risk of developing long COVID through July 2022, using pre-infection symptoms and functional status as exposures. The comparator group consisted of individuals with none of the post-infection symptoms, while the long COVID group included 40,655 participants with at least one post-infection symptom, compared to 24,809 who had none.

The study found that adjusted odds of developing long COVID increased with older age, female sex, Black racial identity, earlier variant, non-vaccination, lower pre-infection self-reported mental and cognitive health, and the number of pre-infection symptoms. Conversely, adjusted odds were not significantly affected by any single pre-infection symptom, self-rated physical ability, or EHR-derived indicators of prior functional impairment. Additionally, no significant differences in risk were observed based on pre-infection total incidences of long COVID symptoms.

Safety and tolerability data, including adverse events or discontinuations, were not reported. The study noted that the impacts of co-occurring pre-infection symptoms require further investigation. Causality was not explicitly claimed; the findings reflect adjusted odds representing association rather than direct causation. Both harmonized electronic health records data and patient-reported outcomes contribute important data for developing the diagnostic utility of functional status changes in long COVID.

Did you know that your health before a virus infection might predict your risk of long COVID? This large study looked at over 65,000 U.S. adults in the All of Us Research Program to answer that question. They wanted to understand if symptoms or functional issues before getting sick made long-term problems more likely. The team followed these people through July 2022 to see who developed long COVID. They found that older age, female sex, Black racial identity, and having fewer vaccines before infection were linked to higher risk. People who reported lower mental or cognitive health before getting sick also faced higher odds of developing long-term symptoms.

long COVID is a complex condition where symptoms linger after the initial infection. The study showed that the total number of symptoms a person had before getting sick mattered. Those with more pre-infection issues were more likely to develop long COVID later. However, looking at just one specific symptom before infection did not significantly change the risk. Even indicators of physical ability from medical records did not predict the outcome on their own. This suggests that the overall picture of a person's health matters more than isolated details.

The researchers also noted that they need to investigate how different pre-infection symptoms work together. They did not find serious safety issues or side effects because this was an observational study, not a drug trial. The main takeaway is that both medical records and what patients report about their health are vital for understanding long COVID. This study helps us see that long-term illness is linked to changes in baseline functioning, including in people who had symptoms before they even got infected.

What this means for you:
Overall pre-infection health patterns, not single symptoms, predict long COVID risk.

Study Details

Study typeCohort
Sample sizen = 65,464
EvidenceLevel 3
PublishedApr 2026
View Original Abstract ↓
ABSTRACT IMPORTANCE: Over seven million U.S. adults experience persistent health issues after COVID-19, known as long COVID. Although multiple guidelines recommend the inclusion of functional status in long COVID diagnostic criteria, more evidence is needed to guide this recommendation. This study explored the adjusted odds of developing long COVID by pre-infection symptoms and functional status, and the feasibility of estimating functional status using health records data. DESIGN & METHODS: Retrospective cohort study of U.S. adults with history of COVID-19 enrolled in a multicenter national cohort study through July 2022 (All of Us Controlled Tier CDR 7.0), using diagnostic, procedure, and billing codes from the health record, and baseline survey responses. The risk of long COVID was estimated using logistic regression by pre-infection (-5 years) incidences of (a) at least one symptom common in long COVID, and (b) functional status, and adjusted for disease and demographic characteristics. RESULTS: N = 65,464 met inclusion criteria; n=40,655 had post-infection occurrences of at least one symptom (long COVID group), n=24,809 had none (recovered). Adjusted odds ratios of developing long COVID increased with older age, female sex, Black racial identity, earlier variant, non-vaccination, lower pre-infection self-reported mental and cognitive health, and number of pre-infection symptoms. Adjusted odds were not significantly affected by any single pre-infection symptom, self-rated physical ability, or EHR-derived indicators of prior functional impairment. CONCLUSIONS. In this model, there were no significant differences in risk of long COVID based on either pre-infection total incidences of long COVID symptoms (compared to the average of 4) or pre-infection functional impairment. This suggests that long COVID was associated with a change from baseline functioning and health, including in people with pre-infection incident symptoms and functional impairments. The impacts of co-occurring pre-infection symptoms requires further investigation. Both harmonized electronic health records data and patient-reported outcomes contribute important data for developing the diagnostic utility of functional status changes in long COVID.
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