Severe Fatigue and Persistent Symptoms at 3 Months Following Severe Acute Respiratory Syndrome Coronavirus 2 Infections During the Pre-Delta, Delta, and Omicron Time Periods: A Multicenter Prospective Cohort Study
Michael Gottlieb, Ralph C. Wang, Huihui Yu, Erica S. Spatz, Juan Carlos C. Montoy, Robert M. Rodriguez, Anna Marie Chang, Joann G. Elmore, Paavali Hannikainen, Mandy J. Hill, Ryan Huebinger, Ahamed H. Idris, Zhenqiu Lin, Katherine Koo, Samuel McDonald, Kelli N. O’Laughlin, Ian D. Plumb, Michelle Santangelo, Sharon Saydah, Michael Willis, Lauren E. Wisk, Arjun K. Venkatesh, Kari A. Stephens, Robert A. Weinstein, for the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) Group, Robert A. Weinstein, Michael Gottlieb, Michelle Santangelo, Katherine Koo, Antonia Derden, Michael Gottlieb, Kristyn Gatling, Diego Cordero, Geoffrey Yang, Marshall Kaadan, Minna Hassaballa, Ryan Jerger, Zohaib Ahmed, Michael Choi, Arjun Venkatesh, Erica Spatz, Zhenqiu Lin, Shuxia Li, Huihui Yu, Imtiaz Ebna Mannan, Zimo Yang, Arjun Venkatesh, Erica Spatz, Andrew Ulrich, Jeremiah Kinsman, Jocelyn Dorney, Senyte Pierce, Xavier Puente, Graham Nichol, Kari A. Stephens, Jill Anderson, Dana Morse, Karen Adams, Zenoura Maat, Tracy Stober, Kelli N. O’Laughlin, Nikki Gentile, Rachel E Geyer, Michael Willis, Luis Ruiz, Kerry Malone, Jasmine Park, Kristin L. Rising, Efrat Kean, Morgan Kelly, Kevin Schaeffer, Paavali Hannikainen, Lindsey Shughart, Hailey Shughart, Nicole Renzi, Grace Amadio, Dylan Grau, Phillip B. Watts, David Cheng, Jessica Miao, Carly Shutty, Alex Charlton, Mandy J. Hill, Ryan Huebinger Site, Summer Chavez, Arun Kane, Peter Nikonowicz, Ahamed H. Idris, Samuel McDonald, David Gallegos, Riley Martin, Joann G. Elmore, Lauren E. Wisk, Michelle L’Hommedieu, Christopher W Chandler, Megan Eguchi, Kate Diaz Roldan, Raul Moreno, Robert M. Rodriguez, Ralph C. Wang
Abstract
BACKGROUND: Most research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants focuses on initial symptomatology with limited longer-term data. We characterized prevalences of prolonged symptoms 3 months post-SARS-CoV-2 infection across 3 variant time-periods (pre-Delta, Delta, and Omicron). METHODS: This multicenter prospective cohort study of adults with acute illness tested for SARS-CoV-2 compared fatigue severity, fatigue symptoms, organ system-based symptoms, and ≥3 symptoms across variants among participants with a positive ("COVID-positive") or negative SARS-CoV-2 test ("COVID-negative") at 3 months after SARS-CoV-2 testing. Variant periods were defined by dates with ≥50% dominant strain. We performed multivariable logistic regression modeling to estimate independent effects of variants adjusting for sociodemographics, baseline health, and vaccine status. RESULTS: The study included 2402 COVID-positive and 821 COVID-negative participants. Among COVID-positives, 463 (19.3%) were pre-Delta, 1198 (49.9%) Delta, and 741 (30.8%) Omicron. The pre-Delta COVID-positive cohort exhibited more prolonged severe fatigue (16.7% vs 11.5% vs 12.3%; P = .017) and presence of ≥3 prolonged symptoms (28.4% vs 21.7% vs 16.0%; P < .001) compared with the Delta and Omicron cohorts. No differences were seen in the COVID-negatives across time-periods. In multivariable models adjusted for vaccination, severe fatigue and odds of having ≥3 symptoms were no longer significant across variants. CONCLUSIONS: Prolonged symptoms following SARS-CoV-2 infection were more common among participants infected during pre-Delta than with Delta and Omicron; however, these differences were no longer significant after adjusting for vaccination status, suggesting a beneficial effect of vaccination on risk of long-term symptoms. Clinical Trials Registration. NCT04610515.