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
Authors: Gottlieb Michael , Wang Ralph C , Yu Huihui , Spatz Erica S , Montoy Juan Carlos C , Rodriguez Robert M , Chang Anna Marie , Elmore Joann G , Hannikainen Paavali A , Hill Mandy , Huebinger Ryan M , Idris Ahamed H , Lin Zhenqiu , Koo Katherine , McDonald Samuel , O’Laughlin Kelli N , Plumb Ian D , Santangelo Michelle , Saydah Sharon , Willis Michael , Wisk Lauren E , Venkatesh Arjun , Stephens Kari A , Weinstein Robert A ,   for the Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) Group, Weinstein Robert A , Gottlieb Michael , Santangelo Michelle , Koo Katherine , Derden Antonia , Gottlieb Michael , Gatling Kristyn , Guzman Diego , Yang Geoffrey , Kaadan Marshall , Hassaballa Minna , Jerger Ryan , Ahmed Zohaib , Choi Michael , Venkatesh Arjun , Spatz Erica , Lin Zhenqiu , Li Shu-Xia , Yu Huihui , Mannan Imtiaz Ebna , Yang Zimo , Venkatesh Arjun , Spatz Erica , Ulrich Andrew , Kinsman Jeremiah , Dorney Jocelyn , Pierce Senyte , Puente Xavier , Nichol Graham , Stephens Kari , Anderson Jill , Morse Dana , Adams Karen , Maat Zenoura , Stober Tracy , O'Laughlin Kelli N , Gentile Nikki , Geyer Rachel E , Willis Michael , Ruiz Luis , Malone Kerry , Park Jasmine , Rising Kristin , Kean Efrat , Kelly Morgan , Schaeffer Kevin , Hannikainen Paavali , Shughart Lindsey , Shughart Hailey , Renzi Nicole , Amadio Grace , Grau Dylan , Watts Phillip , Cheng David , Miao Jessica , Shutty Carly , Charlton Alex , Hill Mandy , Site Ryan Huebinger , Chavez Summer , Kane Arun , Nikonowicz Peter , Idris Ahamed H , McDonald Samuel , Gallegos David , Martin Riley , Elmore Joann G , Wisk Lauren E , L'Hommedieu Michelle , Chandler Christopher W , Eguchi Megan , Roldan Kate Diaz , Moreno Raul , Rodriguez Robert M , Wang Ralph C , Montoy Juan Carlos C , Kemball Robin , Chan Virginia , Chavez Cecilia Lara , Wong Angela , Arreguin Mireya , Plumb Ian D , Hall Aron J , Saydah Sharon , Briggs-Hagen Melissa 
Published: January 2023

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 &lt; .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.