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Multicenter Study
. 2023 Jun 8;76(11):1930-1941.
doi: 10.1093/cid/ciad045.

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  1 , Ralph C Wang  2 , Huihui Yu  3   4 , Erica S Spatz  3   5 , Juan Carlos C Montoy  2 , Robert M Rodriguez  6 , Anna Marie Chang  7 , Joann G Elmore  8 , Paavali A Hannikainen  9 , Mandy Hill  10 , Ryan M Huebinger  10 , Ahamed H Idris  11 , Zhenqiu Lin  3   4 , Katherine Koo  12 , Samuel McDonald  11   13 , Kelli N O'Laughlin  14 , Ian D Plumb  15 , Michelle Santangelo  12 , Sharon Saydah  15 , Michael Willis  14 , Lauren E Wisk  8 , Arjun Venkatesh  3   16 , Kari A Stephens  17   18 , Robert A Weinstein  12   19 ; Innovative Support for Patients with SARS-CoV-2 Infections Registry (INSPIRE) Group
Collaborators, Affiliations
Multicenter Study

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 et al. Clin Infect Dis. .

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.

Keywords: COVID-19; Delta; Long COVID; Omicron; SARS-CoV-2.

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Conflict of interest statement

Potential conflicts of interest. M. G. reports the following institutional funding: Rush Center for Emerging Infectious Diseases Research Grant, Society for Academic Emergency Medicine Grant, Emergency Medicine Foundation/Council of Residency Directors in Emergency Medicine Education Research Grant, Emergency Medicine: Reviews and Perspectives Medical Education Research Grant, and University of Ottawa Department of Medicine Education Grant. E. S. S. receives grant funding from the National Institute on Minority Health and Health Disparities (U54MD010711-01), the US Food and Drug Administration (FDA) to support projects within the Yale–Mayo Clinic Center of Excellence in Regulatory Science and Innovation (U01FD005938), the National Institute of Biomedical Imaging and Bioengineering (R01 EB028106-01), and the National Heart, Lung, and Blood Institute (R01HL151240); and has received honorarium paid to author for a 1-day educational session from Regeneron. J. G. E. reports serving as Editor in Chief of Adult Primary Care topics for UpToDate. A. V. reports funding for coronavirus disease 2019 (COVID-19)–related studies from the Society of Academic Emergency Medicine Foundation Emerging Infectious Disease and Preparedness Grant, the Agency for Healthcare Research and Quality (R01 HS 28340-01), the FDA (ID: 75F40120C00174), and the Emergency Medicine Health Policy Institute/Emergency Medicine Foundation; grants or contracts from the American Board of Emergency Medicine National Academy of Medicine Fellowship, Centers for Medicare and Medicaid Services, National Institute on Drug Abuse, Moore Foundation, Genentech, and FORE Foundation; consulting fees from Liminal Sciences; payment for expert testimony from Salvi, Shostok & Pritchard; support for attending meetings and/or travel from the American College of Emergency Physician, and stock or stock options with Hyperfine Inc/Liminal Sciences. A. H. I. reports participation on a data and safety monitoring board (DSMB) or advisory board for Stryker, Inc. A. M. C. reports grants or contracts from the CDC, unrelated to this work. L. E. W. reports participation on a DSMB or advisory board for a diabetes project at University of Washington. R. R. reports a grant from the National Institute of Allergy and Infectious Diseases (R01 AI166967-01, all payments made to the University of California, San Francisco). R. A. W. reports consulting fees from UpToDate as a reviewer for infection control sections, and participation as unpaid member of a scientific advisory board for the European Clinical Research Alliance on Infectious Diseases Foundation. S. M. reports an NIH Institutional Training Grant (5KL2TR003981-02), not related to the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Patient flow diagram. Abbreviations: COVID–, negative test for severe acute respiratory syndrome coronavirus 2; COVID+, positive test for severe acute respiratory syndrome coronavirus 2.
Figure 2.
Figure 2.
Three-month symptom prevalence and adjusted odds ratios by variants at 3 months among study participants with a positive severe acute respiratory syndrome coronavirus 2 test (COVID+). Model 1 accounted for sociodemographics (age, gender, race, ethnicity), 9 preexisting conditions (specified in Table 1), and hospitalization for coronavirus disease 2019. Pre-Delta was considered as the reference variant period for Delta and Omicron. If the 95% confidence intervals (CIs) included 1, the difference between the paired variant periods was not statistically significant. If the 95% CIs excluded 1, then the risk of adverse outcome in the compared variant period was significantly lower or higher than the reference variant period. The statistically significant difference between Omicron and Delta was based on post hoc test results. Abbreviations: CI, confidence interval; COVID+, positive test for severe acute respiratory syndrome coronavirus 2; HEENT, head/ears/eyes/nose/throat; OR, odds ratio.
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