Symptom Burden and Immune Dynamics 6 to 18 Months Following Mild Severe Acute Respiratory Syndrome Coronavirus 2 Infection (SARS-CoV-2): A Case-control Study

Elisabeth B Fjelltveit, Bjørn Blomberg, Kanika Kuwelker, Fan Zhou, Therese B Onyango, Karl A Brokstad, Rebecca Elyanow, Ian M Kaplan, Camilla Tøndel, Kristin G I Mohn, Türküler Özgümüş, Rebecca J Cox, Nina Langeland, Bergen COVID-19 Research Group, Geir Bredholt, Lena Hansen, Sarah Larteley Lartey, Anders Madsen, Jan Stefan Olofsson, Sonja Ljostveit, Marianne Sævik, Hanne Søyland, Helene Heitmann Sandnes, Nina Urke Ertesvåg, Juha Vahokoski, Amit Bansal, Håkon Amdam, Tatiana Fomina, Dagrun Waag Linchausen, Synnøve Hauge, Annette Corydon, Silje Sundøy, Elisabeth B Fjelltveit, Bjørn Blomberg, Kanika Kuwelker, Fan Zhou, Therese B Onyango, Karl A Brokstad, Rebecca Elyanow, Ian M Kaplan, Camilla Tøndel, Kristin G I Mohn, Türküler Özgümüş, Rebecca J Cox, Nina Langeland, Bergen COVID-19 Research Group, Geir Bredholt, Lena Hansen, Sarah Larteley Lartey, Anders Madsen, Jan Stefan Olofsson, Sonja Ljostveit, Marianne Sævik, Hanne Søyland, Helene Heitmann Sandnes, Nina Urke Ertesvåg, Juha Vahokoski, Amit Bansal, Håkon Amdam, Tatiana Fomina, Dagrun Waag Linchausen, Synnøve Hauge, Annette Corydon, Silje Sundøy

Abstract

Background: The burden and duration of persistent symptoms after nonsevere coronavirus disease 2019 (COVID-19) remains uncertain. This study aimed to assess postinfection symptom trajectories in home-isolated COVID-19 cases compared with age- and time- matched seronegative controls, and investigate immunological correlates of long COVID.

Methods: A prospective case-control study included home-isolated COVID-19 cases between February 28 and April 4, 2020, and followed for 12 (n = 233) to 18 (n = 149) months, and 189 age-matched severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naive controls. We collected clinical data at baseline, 6, 12, and 18 months postinfection, and blood samples at 2, 4, 6, and 12 months for analysis of SARS-CoV-2-specific humoral and cellular responses.

Results: Overall, 46% (108/233) had persisting symptoms 12 months after COVID-19. Compared with controls, adult cases had a high risk of fatigue (27% excess risk, sex, and comorbidity adjusted odds ratio [aOR] 5.86; 95% confidence interval [CI], 3.27-10.5), memory problems (21% excess risk; aOR 7.42; CI, 3.51-15.67), concentration problems (20% excess risk; aOR 8.88; 95% CI, 3.88-20.35), and dyspnea (10% excess risk; aOR 2.66; 95% CI, 1.22-5.79). The prevalence of memory problems increased overall from 6 to 18 months (excess risk 11.5%; 95% CI, 1.5-21.5; P = .024) and among women (excess risk 18.7%; 95% CI, 4.4-32.9; P = .010). Longitudinal spike immunoglobulin G was significantly associated with dyspnea at 12 months. The spike-specific clonal CD4+ T-cell receptor β depth was significantly associated with both dyspnea and number of symptoms at 12 months.

Conclusions: This study documents a high burden of persisting symptoms after mild COVID-19 and suggests that infection induced SARS-CoV-2-specific immune responses may influence long-term symptoms.

Keywords: PASC; SARS CoV-2; T-cells; antibodies; long COVID.

Conflict of interest statement

Potential conflicts of interest. R.C. declares receipt of a research grant to the University of Bergen from Trond Mohn Stiftelse (TMS2020TMT05) and from the Helse-Vest to Haukeland University Hospital (F11628). N.L. declares receipt of a research grant from the Regional Health Authority of Western Norway and reports roles as Member of Faculty Board, NTNU, Trondheim, Norway, and as Member of the Board, Stavanger University Hospital, Stavanger, Norway. K.M. declares receipt of research grant from Helse-Vest (F12626). R.E. and I.M.K. declare employment and equity ownership with Adaptive Biotechnologies. The remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Study population. Inclusion of SARS-CoV-2 cases (left) and control group (right). Eligible participants tested for SARS-CoV-2 infection by RT-PCR at Bergen Municipality Emergency Clinic (BMEC) were recruited between February 28 and April 4, 2020. Only 1 case (the first most symptomatic) from each household was tested because of the limited testing capacity; thus, individuals living with COVID-19-positive study participants were included as household contacts. If household contact had positive SARS-CoV-2 serology (RBD and spike-IgG ELISA) within 2 months after recruitment, they were registered as cases. Seronegative household contact without a history of COVID-19 symptoms were included as controls. Additional controls were recruited amongst individuals who were prioritized for vaccination, either because of their age, comorbidity, or occupation. At the time of symptom recording, all controls were confirmed seronegative. COVID-19, coronavirus disease 2019; ELISA, enzyme-linked immunosorbent assay; LTF,lost to follow-up; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 2.
Figure 2.
Age-stratified symptom prevalence at 12 months after infection. Bar plot representing the proportion of cases reporting 11 key symptoms at 12 months’ follow-up. The cases reported a mean of 1.4 symptoms overall. The age group 0 to 15 years old (n = 13) is not shown because of absence of symptoms. The light gray area in the bar charts represents the overall proportion with any of the 11 symptoms in the current age group. The colored areas represent the proportion with the specified symptoms.
Figure 3.
Figure 3.
Longitudinal symptom changes up to 18 months after infection. Dumbbell charts present longitudinal data on development of 11 specified symptoms in a subcohort of patients followed for 18 months (n = 148, 1 patient was excluded because of missing data on all symptoms at 6 months). (Left panel) The overall symptom change from 6 to 12 months, (Middle panel) the overall symptom change from 6 to 18 months, and (Right panel) the symptom change in men (n = 73) and women (n = 75) from 6 to 18 months.
Figure 4.
Figure 4.
Kinetics of the spike IgG antibody response in relation to symptoms at 6 and 12 months. The relationship between longitudinal antibody titers and (A) persistent dyspnea versus no dyspnea, (B) 3 or more symptoms at 12 months vs no symptoms, and (C) persistent fatigue vs no fatigue. The generalized estimating equation (GEE) coefficients with 95% confidence intervals (CI) are adjusted for age, sex, comorbidity, and time of measurement. All cases who had been vaccinated against SARS-CoV-2 during the follow-up period (n = 20) were excluded from the analysis of immunological parameters at 12 months. IgG, immunoglobulin G; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

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Source: PubMed

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