Differences in Long COVID severity by duration of illness, symptom evolution, & vaccination: longitudinal cohort study from INSPIRE group,'25,Gottlieb

https://www.thelancet.com/journals/lanam/article/PIIS2667-193X(25)00036-5/fulltext

Articles
Volume 44
101026 April 2025 Open access
Differences in Long COVID severity by duration of illness, symptom evolution, and vaccination: a longitudinal cohort study from the INSPIRE group
Michael Gottlieb MichaelGottliebMD@Gmail.com ∙
Huihui YuJi Chen Erica S. Spatz Nicole L. Gentile Rachel E. Geyer
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Summary

Background
Although short-term outcomes of Long COVID have been described, longer-term physical and mental health outcomes of Long COVID are less well-established. This study sought to assess differences in long-term physical and mental health outcomes extending up to three years among those with current, resolved, and no Long COVID, as well as duration of Long COVID and vaccination status.

Methods
This was a prospective, multisite, study of participants with SARS-CoV-2 infection from 12/7/2020-8/29/2022, with data collected through 4/2/2024. Surveys included validated tools for physical and mental health. Data were analyzed by Long COVID status (never-had, resolved, current), Long COVID duration and vaccination status.

Findings
Of 3663 participants, 2604 (71.1%) never had Long COVID, 994 (27.1%) reported current Long COVID, and 65 (1.8%) reported resolved Long COVID. Compared to never having Long COVID, current Long COVID had lower/worse scores for Patient-Reported Outcomes Measurement Information System (PROMIS) version 29 Physical (7.8; 95% confidence interval [CI] 7.3–8.3) and Mental Health (9.4; 95% CI 8.8–10.1) and higher likelihood of moderate-to-high stress (adjusted odds ratio [aOR]: 2.0; 95% CI 1.6–2.4), moderate-to-high loneliness (aOR: 1.6; 95% CI 1.4–2.0), moderate-to-severe fatigue (aOR: 3.0; 95% CI 2.5–3.7), insufficient activity (aOR for Speedy Nutrition and Physical Activity Assessment ≤4: 0.6; 95% CI 0.5–0.7; aOR for Exercise Vital Sign ≤150 min/week: 0.7, 95% CI 0.6–1.0), and worse dyspnea (aOR: 5.0; 95% CI 4.3–5.8). Resolved Long COVID had lower scores for PROMIS Physical by 2.0 (95% CI 0.2–3.8) and Mental Health by 2.3 (95% CI 0.2–4.4) than the never-had-Long COVID cohort. Number of COVID-19 vaccinations was associated with better outcomes across all measures.

Interpretation
Among participants followed up to 3 years after initial infection, those with current Long COVID had worse physical and mental health outcomes. The majority of those with Long COVID did not resolve, with less than 2% having resolved Long COVID. The resolved Long COVID cohort had moderately worse physical and mental health compared with those never-having-Long COVID. COVID-19 vaccination was associated with better outcomes.

Funding
Centers for Disease Control and Prevention.

Keywords

1. SARS-CoV-2
2. Long COVID
3. PROMIS
4. Physical health
5. Mental health

Research in context
Evidence before this study
Research has demonstrated the occurrence of prolonged symptoms after an initial infection with SARS-CoV-2, often referred to as Long COVID. However, much of this research has primarily focused on shorter-term outcomes of Long COVID, with most studies evaluating outcomes at 3–6 months. Data have demonstrated that symptoms evolve over time and it is believed that symptoms in the shorter-term may not reflect those later in the Long COVID condition. Despite this, there remains limited research focusing on longer-term outcomes and scant research among those who have reported resolution of their Long COVID illness. Therefore, there is a need to better understand the longer-term outcomes among those with Long COVID, as well as the influence of Long COVID length and vaccination on the longer-term outcomes. We conducted a search of PubMed using terms of “COVID”, “Long COVID”, “SARS-CoV-2”, “post-infectious sequelae”, and “longer-term” in October 2024. While we identified many studies on Long COVID outcomes, most studies included data from 3 to 12 months, with limited data beyond this period.

Added value of this study
We followed a population affected with SARS-CoV-2 for up to 3 years after initial infection and analyzed differences in physical and mental health among those with current, resolved, and no history of Long COVID. We further analyzed this by length of Long COVID and COVID-19 vaccination. A key strength of this study was prospective data collection using validated tools obtained directly from participants. Another strength was the length of the study, allowing key findings regarding the physical and mental health status among those with Long COVID extending to 3 years. Additionally, we were able to analyze physical and mental health among those with resolved Long COVID, which is an understudied population. Finally, we analyzed differences by length of Long COVID and vaccination dose number, to identify key predictors of illness severity.

Implications of all the available evidence
The results of our study add to the understanding of Long COVID by providing data on the physical and mental health outcomes among those with Long COVID extending to 3 years after their initial SARS-CoV-2 infection. The overall rate of Long COVID resolution was less than 2% in our population, with a mean duration of over 2 years. We identified significantly worse physical and mental health outcomes among those with current Long COVID, while those with resolved Long COVID had worse physical and mental health outcomes than those who never had Long COVID. We also identified better long-term outcomes among those receiving COVID-19 vaccination, that was higher among those receiving more total vaccinations. Understanding these differences is crucial to developing targeted interventions and improving patient care.

 

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