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. 2025 Feb 14:44:101026.
doi: 10.1016/j.lana.2025.101026. eCollection 2025 Apr.

Differences in Long COVID severity by duration of illness, symptom evolution, and vaccination: a longitudinal cohort study from the INSPIRE group

Michael Gottlieb  1 , Huihui Yu  2   3 , Ji Chen  2   3 , Erica S Spatz  2   3 , Nicole L Gentile  4   5 , Rachel E Geyer  4 , Michelle Santangelo  1 , Caitlin Malicki  6 , Kristyn Gatling  7 , Sharon Saydah  8 , Kelli N O'Laughlin  9 , Kari A Stephens  4 , Joann G Elmore  10 , Lauren E Wisk  10 , Michelle L'Hommedieu  10 , Robert M Rodriguez  11 , Juan Carlos C Montoy  11 , Ralph C Wang  11 , Kristin L Rising  12   13 , Efrat Kean  12   13 , Jonathan W Dyal  14 , Mandy J Hill  15 , Arjun K Venkatesh  3   6 , Robert A Weinstein  7   16
Affiliations

Differences in Long COVID severity by duration of illness, symptom evolution, and vaccination: a longitudinal cohort study from the INSPIRE group

Michael Gottlieb et al. Lancet Reg Health Am. .

Abstract

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: Long COVID; Mental health; PROMIS; Physical health; SARS-CoV-2.

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Conflict of interest statement

Michael Gottlieb reports funding from Society for Academic Emergency Medicine Foundation Emerging Infectious Disease and Preparedness Grant. Nicole L. Gentile reports funding from Improving Access to Multidisciplinary Care for Patients with Long COVID (AHRQ, U18 HS29905-01), Pain Relief with Integrative Medicine (PRIMe)?: Feasibility Trial of Acupuncture for Long COVID (NCCIH, R34AT012679-01), Interaction between SARS-CoV-2 Infection and Ancestral genomic Variations in the Risk of Alzheimer's Disease and Related Disorders (ISAVRAD) (NIA, U19 AG076581-01A1), Post-Acute Sequelae of SARS-CoV-2 (PASC): Analysis of Autoantibody Abnormalities and Impact of Pain on Quality of Life and Function Royalty Research Fund – University of Washington. Rachel E. Geyer reports funding from Improving Access to Multidisciplinary Care for Patients with Long COVID (AHRQ, U18 HS29905-01), Pain Relief with Integrative Medicine (PRIMe)?: Feasibility Trial of Acupuncture for Long COVID (NCCIH, R34AT012679-01), Post-Acute Sequelae of SARS-CoV-2 (PASC): Analysis of Autoantibody Abnormalities and Impact of Pain on Quality of Life and Function Royalty Research Fund – University of Washington UW Core Center for Clinical Research (CCCR) of Musculoskeletal Conditions (NIH, P30 AR072572-08). Joann G Elmore serves as Editor-In-Chief for adult general medicine topics at UpToDate. Ralph C Wang reports funding from the SAEM Foundation Emerging Infectious Disease and Preparedness Grant. Kristin Rising reports funding from the Preventing Emerging Infections Through Vaccine Effectiveness Testing (Project PREVENT) II (CDC U01CK00048), PROmotion of COVid-19 VA(X)ccination in the Emergency Department (PROCOVAXED; NIH 1R01AI66967), and the COVID-19 Mobile Vaccination Program – Philadelphia Department of Public Health. Arjun K Venkatesh reports funding from Society for Academic Emergency Medicine Foundation Emerging Infectious Disease and Preparedness Grant. All authors received institutional funding from the Centers for Disease Control and Prevention (75D30120C08008) for the conduct of this study.

Figures

Fig. 1
Fig. 1
Linear regression modeling results of the continuous outcomes for adjusted estimated differences in outcomes by Long COVID status. Adjustment included age and sex.
Fig. 2
Fig. 2
Logistic regression modeling results of dichotomous outcomes for adjusted estimated differences in outcomes by Long COVID status. Higher odds for perceived stress scale scores ≥14, UCLA loneliness scale scores ≥35, or fatigue severity scale scores ≥36 indicate worse outcomes; higher odds for SNAP scores = 4 or EVS ≥150 min/week indicates better outcomes; Adjustment included age and sex.
Fig. 3
Fig. 3
Cumulative logit modeling results of the ordinal outcome for adjusted estimated differences in outcomes by Long COVID status. Higher odds for higher MMRC dyspnea scale scores indicate worse outcomes; MMRC, Modified Medical Research Council; Adjustment included age and sex.
Fig. 4
Fig. 4
Linear regression modeling results of the continuous outcomes for the impact of Long COVID duration among participants with current Long COVID. Adjustment included age and sex.
Fig. 5
Fig. 5
Logistic regression modeling results of dichotomous outcomes and cumulative logit modeling results for MMRC ordinal outcome for the impact of Long COVID duration among participants with current Long COVID. Higher odds for perceived stress scale scores ≥14, UCLA loneliness scale scores ≥35, or fatigue severity scale scores ≥36 indicate worse outcomes; higher odds for SNAP scores = 4 or EVS ≥150 min/week indicates better outcomes; Higher odds for higher MMRC dyspnea scale scores indicate worse outcomes; MMRC, Modified Medical Research Council; Adjustment included age and sex.
Fig. 6
Fig. 6
Linear regression modeling results of the continuous outcomes for the impact of COVID-19 vaccination before Long COVID onset on outcomes among participants with current Long COVID. Adjustment included age and sex.
Fig. 7
Fig. 7
Logistic regression modeling results of dichotomous outcomes and Cumulative logit modeling results for MMRC ordinal outcome for the impact of COVID-19 vaccination before Long COVID onset on outcomes among participants with current Long COVID. Higher odds for perceived stress scale scores ≥14, UCLA loneliness scale scores ≥35, or fatigue severity scale scores ≥36 indicate worse outcomes; higher odds for SNAP scores = 4 or EVS ≥150 min/week indicates better outcomes; Higher odds for higher MMRC dyspnea scale scores indicate worse outcomes; MMRC, Modified Medical Research Council; Adjustment included age and sex.
Fig. 8
Fig. 8
Health outcomes among all participants by COVID-19 vaccine dose count. EVS, exercise vital sign; SNAP, Speedy Nutrition and Physical Activity.
See this image and copyright information in PMC

References

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