A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings

Abstract

Background: A substantial proportion of persons who develop COVID-19 report persistent symptoms after acute illness. Various pathophysiologic mechanisms have been implicated in the pathogenesis of postacute sequelae of SARS-CoV-2 infection (PASC).

Objective: To characterize medical sequelae and persistent symptoms after recovery from COVID-19 in a cohort of disease survivors and controls.

Design: Cohort study. (ClinicalTrials.gov: NCT04411147).

Setting: National Institutes of Health Clinical Center, Bethesda, Maryland.

Participants: Self-referred adults with laboratory-documented SARS-CoV-2 infection who were at least 6 weeks from symptom onset were enrolled regardless of presence of PASC. A control group comprised persons with no history of COVID-19 or serologic evidence of SARS-CoV-2 infection, recruited regardless of their current health status. Both groups were enrolled over the same period and from the same geographic area.

Measurements: All participants had the same evaluations regardless of presence of symptoms, including physical examination, laboratory tests and questionnaires, cognitive function testing, and cardiopulmonary evaluation. A subset also underwent exploratory immunologic and virologic evaluations.

Results: 189 persons with laboratory-documented COVID-19 (12% of whom were hospitalized during acute illness) and 120 antibody-negative control participants were enrolled. At enrollment, symptoms consistent with PASC were reported by 55% of the COVID-19 cohort and 13% of control participants. Increased risk for PASC was noted in women and those with a history of anxiety disorder. Participants with findings meeting the definition of PASC reported lower quality of life on standardized testing. Abnormal findings on physical examination and diagnostic testing were uncommon. Neutralizing antibody levels to spike protein were negative in 27% of the unvaccinated COVID-19 cohort and none of the vaccinated COVID-19 cohort. Exploratory studies found no evidence of persistent viral infection, autoimmunity, or abnormal immune activation in participants with PASC.

Limitations: Most participants with COVID-19 had mild to moderate acute illness that did not require hospitalization. The prevalence of reported PASC was likely overestimated in this cohort because persons with PASC may have been more motivated to enroll. The study did not capture PASC that resolved before enrollment.

Conclusion: A high burden of persistent symptoms was observed in persons after COVID-19. Extensive diagnostic evaluation revealed no specific cause of reported symptoms in most cases. Antibody levels were highly variable after COVID-19.

Primary funding source: Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

Visual Abstract.. A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings.

A substantial proportion of persons who develop COVID-19 experience postacute sequelae of SARS-CoV-2 infection (PASC). This article reports baseline findings from an ongoing longitudinal cohort study that seeks to characterize the risk factors, clinical findings, laboratory features, and natural history of PASC.

Appendix Figure.. Study flow diagram.

Figure 1.. Risk factors and associations with PASC.

6MWT = 6-minute walk test distance (in meters); BMI = body mass index; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate; GAD-2 = Generalized Anxiety Disorder-2; MCS = mental component summary; NF-L = neurofilament light chain; NIH = National Institutes of Health; PASC = postacute sequelae of SARS-CoV-2 infection; PCS = physical component summary; PFT = pulmonary function test; PHQ-2 = Patient Health Questionnaire-2; pro-BNP = pro–B-type natriuretic peptide; SF-36 = Short Form-36 Health Survey (version 2). A. Odds ratios with 95% CIs quantifying univariate associations between pre–COVID-19 characteristics and presence of any PASC at the baseline visit. Mood disorders include bipolar disorder and depression. B. Odds ratios with 95% CIs quantifying univariate associations between results of diagnostic testing done at the baseline visit and presence of any PASC. C. Odds ratios with 95% CIs quantifying univariate associations between scores on health surveys completed by participants at the baseline visit and presence of PASC.

Figure 2.. Characterization of immune parameters in study participants.

PASC = postacute sequelae of SARS-CoV-2 infection; T_EM = effector memory T cells. A. Plasma levels of granzyme B among study participants. P values were calculated using the Wilcoxon rank-sum test. B. Comparison of the frequency of CD4⁺ CD25⁺ T_EM cells (cluster 6) in the peripheral blood of study participants. P values were calculated using the Wilcoxon rank-sum test. C. Percentage inhibition of angiotensin-converting enzyme 2 (ACE2) receptor binding to the SARS-CoV-2 receptor-binding domain (RBD) in sera from study participants, using a surrogate neutralizing antibody binding assay (17). The dashed line represents the assay cutoff (30% inhibition). “Not vaccinated” refers to participants who had not received a SARS-CoV-2 vaccine dose before study enrollment, and “vaccinated” refers to participants who had received ≥1 SARS-CoV-2 vaccine dose after infection but before study enrollment. P values were calculated using the t test. D. Percentage inhibition of ACE2 receptor binding to the SARS-CoV-2 RBD as a function of time from COVID-19 symptom onset to study enrollment. The dashed line represents the assay cutoff (30% inhibition).