Variable Long COVID Definitions Create Hurdles in Care, Research

A standardized definition of long COVID is necessary to improve diagnostic accuracy, clinical recognition, and research comparability, according to a new study published in JAMA Network Open.1

Long COVID, defined by various major organizations, such as the National Academies of Sciences, Engineering, and Medicine (NASEM), can be characterized by prolonged COVID or respiratory-related symptoms; however, there are numerous discrepancies between existing definitions. These discrepancies pose significant hurdles in recognition by both patients and clinicians, which can result in delayed or unnecessary treatments.1

Long COVID definition variability remains inconsistent, resulting in delayed recognition, documentation, and treatment. | Image Credit: AdobeStock_tilialucida.jpeg

In the new study, researchers observed only 5 common symptoms across data from the Innovative Support for Patients With SARS-CoV-2 Infections Registry (INSPIRE; NCT04610515) and 5 comparator studies, which were “more tired than usual,” “pain or tightness in your chest,” “diarrhea [>3 loose or looser than normal stools in 24 hours],” “decreased smell or change in smell,” and “fatigue, tiredness, or exhaustion.”

“We're not necessarily trying to say that any one definition that we looked at should be used,” lead author Lauren Wisk, PhD, assistant professor in the Division of General Internal Medicine and Health Services Research at the University of California, Los Angeles, said in an interview with The American Journal of Managed Care®. “We were comparing across the ones that exist to sort of see how they stack up, and I think, really importantly, what the implications are for our ability to actually capture people who believe that they have long COVID.”

The longitudinal cohort study INSPIRE consisted of 6044 participants; however, only 75% (n= 4575) were included in this study because they completed the 3-month follow-up survey. Of them, 3521 tested positive for COVID-19. Moreover, 3897 participants (85.2%; 2986 [76.6%] COVID-19 positive) completed both a 3-month and a 6-month follow-up survey, and 3235 (83.0%) of those (2478 [76.6%] COVID-19 positive) also completed the final survey. The remainder were categorized as COVID-19 negative, which included patients with similar COVID or respiratory-related symptoms but who had not received a positive COVID-19 diagnosis. Of participants with race/ethnicity data available (n = 4446), 13.8% were Asian, 8.2% were Black, 68.9% were non-Hispanic White, and 9.1% were labeled as multiracial (5.4%) or of other race (including 0.6% who were Native American or Alaskan Native and 0.5% Native Hawaiian or other Pacific Islander).

The analysis included 5 comparator studies that reported on the prevalence of long COVID at 1 to 5 months post infection, which ranged from 2.6% (84 days [Sudre et al]) to 47.4% (3-5 months [Pagen et al]), and at 6 or more months ranged from 10.0% (95% CI, 8.8%-11.0% [Thaweethai et al]) to 61.9% (6-11 months [Pagen et al]).2-4 When applying the study's long COVID definition to the INSPIRE cohort, the analysis showed a prevalence of long COVID ranging from 0.84% (95% CI, 29.33%-32.40%) to 42.01% (95% CI, 40.37%-43.66%) among the COVID-19–positive group and from 28.08% (95% CI, 25.41%-30.92%) to 40.32% (95% CI, 37.35%-43.36%) among the COVID-19–negative group. However, despite the overlapping rates in prevalence, scientists observed individuals who were COVID-19 positive showed a greater number of symptoms that aligned with multiple definitions of long COVID when compared with individuals who were COVID-19 negative.

The analysis showed that the multiple long COVID definitions tended to identify fewer true long COVID cases (indicating lower sensitivity) but were effective at correctly classifying individuals without long COVID (indicating higher specificity). The study authors concluded that a key identifying factor of long COVID when compared with other post-illness symptoms was the overall symptom count, with long COVID presenting with more symptoms.

Although NASEM did release a long COVID definition, researchers note that it should still be incentivized for federal government clinicians to adopt this definition to help keep diagnoses, documentation, and treatments consistent. However, NASEM includes people who are COVID-19 negative and/or have other post-illness symptoms to identify with long COVID, despite not having it. Wisk attributes this inclusion to expanding access for populations who may not be able to get a COVID-19 test or a provider to administer the test.

“I imagine that was a very intentional decision that they made to try to address some of these access issues… And so, trying to sort of create a little bit more equilibrium around then, who could get access to a long COVID diagnosis,” Wisk said. “But again, there are trade-offs there, and one of them is that we're potentially going to be misdiagnosing people as having long COVID when they potentially have some other condition, including persistent symptoms from another respiratory illness.”

References

1. Wisk LE, L’Hommedieu M, Roldan KD, et al.Variability in long COVID definitions and validation of published prevalence rates. JAMA Netw Open. 2025;8(8):e2526506. doi:10.1001/jamanetworkopen.2025.26506

2. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long COVID. Nat Med. 2021;27(4):626-631. doi:10.1038/s41591-021-01292-y

3. Pagen DME, van Bilsen CJA, Brinkhues S, et al. Prevalence of long-term symptoms varies when using different post-COVID-19 definitions in positively and negatively tested adults: the PRIME post-COVID study. Open Forum Infect Dis. 2023;10(10):ofad471. doi:10.1093/ofid/ofad471

4. Thaweethai T, Jolley SE, Karlson EW, et al. RECOVER Consortium. Development of a definition of postacute sequelae of SARS-CoV-2 infection. JAMA. 2023;329(22):1934-1946. doi:10.1001/jama.2023.8823