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. 2023 May 31:381:e074425.
doi: 10.1136/bmj-2022-074425.

Recovery and symptom trajectories up to two years after SARS-CoV-2 infection: population based, longitudinal cohort study

Tala Ballouz  1 , Dominik Menges  1 , Alexia Anagnostopoulos  1 , Anja Domenghino  1   2 , Hélène E Aschmann  1   3 , Anja Frei  1 , Jan S Fehr  1 , Milo A Puhan  4
Affiliations

Recovery and symptom trajectories up to two years after SARS-CoV-2 infection: population based, longitudinal cohort study

Tala Ballouz et al. BMJ. .

Abstract

Objective: To evaluate longer term symptoms and health outcomes associated with post-covid-19 condition within a cohort of individuals with a SARS-CoV-2 infection.

Design: Population based, longitudinal cohort.

Setting: General population of canton of Zurich, Switzerland.

Participants: 1106 adults with a confirmed SARS-CoV-2 infection who were not vaccinated before infection and 628 adults who did not have an infection.

Main outcome measures: Trajectories of self-reported health status and covid-19 related symptoms between months six, 12, 18, and 24 after infection and excess risk of symptoms at six months after infection compared with individuals who had no infection.

Results: 22.9% (95% confidence interval 20.4% to 25.6%) of individuals infected with SARS-CoV-2 did not fully recover by six months. The proportion of individuals who had an infection who reported not having recovered decreased to 18.5% (16.2% to 21.1%) at 12 months and 17.2% (14.0% to 20.8%) at 24 months after infection. When assessing changes in self-reported health status, most participants had continued recovery (68.4% (63.8% to 72.6%)) or had an overall improvement (13.5% (10.6% to 17.2%)) over time. Yet, 5.2% (3.5% to 7.7%) had a worsening in health status and 4.4% (2.9% to 6.7%) had alternating periods of recovery and health impairment. The point prevalence and severity of covid-19 related symptoms also decreased over time, with 18.1% (14.8% to 21.9%) reporting symptoms at 24 months. 8.9% (6.5% to 11.2%) of participants reported symptoms at all four follow-up time points, while in 12.5% (9.8% to 15.9%) symptoms were alternatingly absent and present. Symptom prevalence was higher among individuals who were infected compared with those who were not at six months (adjusted risk difference 17.0% (11.5% to 22.4%)). Excess risk (adjusted risk difference) for individual symptoms among those infected ranged from 2% to 10%, with the highest excess risks observed for altered taste or smell (9.8% (7.7% to 11.8%)), post-exertional malaise (9.4% (6.1% to 12.7%)), fatigue (5.4% (1.2% to 9.5%)), dyspnoea (7.8% (5.2% to 10.4%)), and reduced concentration (8.3% (6.0% to 10.7%)) and memory (5.7% (3.5% to 7.9%)).

Conclusions: Up to 18% of individuals who were not vaccinated before infection had post-covid-19 condition up to two years after infection, with evidence of excess symptom risk compared with controls. Effective interventions are needed to reduce the burden of post-covid-19 condition. Use of multiple outcome measures and consideration of the expected rates of recovery and heterogeneity in symptom trajectories are important in the design and interpretation of clinical trials.

Registrations: ISRCTN18181860, .

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Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/disclosure-of-interest(available on request from the corresponding author) and declare: funding for the research project by the Department of Health of the canton of Zurich, the University of Zurich Foundation and the Swiss Federal Office of Public Health; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1
Fig 1
Study enrolment into the Zurich SARS-CoV-2 Cohort study (infected individuals)
Fig 2
Fig 2
(A) Proportions and 95% confidence interval of participants who had not recovered (overall) and with mild, moderate, and severe health impairment at months 6, 12, 18, and 24 after infection. Inverse probability of censoring weighting was applied to all estimates. (B) Alluvial plot showing the transition of participants across the different health states over time (among participants with complete data at all time points and excluding those who reported continued recovery at all follow-up time points). The width of the flow corresponds to the weighted proportion of participants and colours represent the overall trajectory between six and 24 months. (C) Proportions and 95% confidence intervals of participants with any symptom (regardless of whether they were related to covid-19) and symptoms reported by participants to be related to covid-19 at months 6, 12, 18, and 24 after infection. Inverse probability of censoring weighting was applied to all estimates. (D) Alluvial plot showing the transition between presence and absence of self-reported covid-19 related symptoms over time (among participants with complete data at all time points and excluding those who were symptom-free at all follow-up time points). The width of the flow corresponds to the weighted proportion of participants and colours represent the overall symptom trajectory between six months and 24 months
Fig 3
Fig 3
Point prevalence and severity of 23 prespecified symptoms at months 6, 12, 18, and 24 after SARS-CoV-2 infection, grouped by body organ system. Error bars show the prevalence and 95% confidence interval for each of the symptoms. Inverse probability of censoring weighting was applied to all estimates. Solid lines refer to symptoms reported by participants to be related to covid-19. Dotted lines refer to all reported symptoms regardless of whether they were reported to be related to covid-19. Stacked bar plots show self-reported severity of symptoms reported to be related to covid-19 (as a proportion of all reported symptoms). PEM=Post-exertional malaise; GI=gastrointestinal
Fig 4
Fig 4
(A) Proportion of SARS-CoV-2 infected participants with fatigue (measured on FAS), dyspnoea grade ≥1 (on mMRC), depression, anxiety, and stress (on DASS-21) over time. (B) Proportion of participants who have not recovered by six months with fatigue (on FAS), dyspnoea grade ≥1 (on mMRC), depression, anxiety, and stress (on DASS-21) over time. (C) Proportion of SARS-CoV-2 infected participants with problems in the five EQ-5D-5L domains over time. (D) Proportion of participants who have not recovered by six months with problems in the five EQ-5D-5L domains over time. Inverse probability of censoring weighting was applied to all estimates. FAS=fatigue assessment scale; mMRC=modified Medical Research Council dyspnoea scale; DASS-21=21 item depression, anxiety and stress scale
Fig 5
Fig 5
Study enrolment into phase 4 Corona Immunitas Zurich seroprevalence study (uninfected comparator group). *Prior or current infection in the Corona Immunitas study was defined as: self-reported positive SARS-CoV-2 PCR or rapid antigen test, positive anti-spike IgG or IgA antibodies with no history of vaccination, or positive anti-nucleocapsid IgG antibodies on enrolment
Fig 6
Fig 6
Observed proportions and excess risk (adjusted absolute risk differences) of each of the symptoms at six months after infection in the infected group (n=1106; Zurich SARS-CoV-2 Cohort) compared with individuals who did not have an infection from the general population (n=628; Corona Immunitas Zurich). Adjusted risk differences were estimated based on inverse probability weighted generalised linear models, adjusted for age, sex, body mass index, smoking status, education level, monthly income, and presence of hypertension, diabetes mellitus, cardiovascular, respiratory, or chronic renal disease, current or past malignancy, and immune suppression
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