Evolution of Coronavirus Disease 2019 (COVID-19) Symptoms During the First 12 Months After Illness Onset

Abstract

Background: Few robust longitudinal data on long-term coronavirus disease 2019 (COVID-19) symptoms are available. We evaluated symptom onset, severity and recovery across the full spectrum of disease severity, up to one year after illness onset.

Methods: The RECoVERED Study is a prospective cohort study based in Amsterdam, the Netherlands. Participants aged ≥18 years were enrolled following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnosis via the local public health service and from hospitals. Standardized symptom questionnaires were completed at enrollment, 1 week and month later, and monthly thereafter. Clinical severity was defined according to World Health Organization (WHO) criteria. Kaplan-Meier methods were used to compare time from illness onset to symptom recovery, by clinical severity. We examined determinants of time to recovery using multivariable Cox proportional hazards models.

Results: Between 11 May 2020 and 1 May 2021, 342 COVID-19 patients (192 [56%] male) were enrolled, of whom 99/342 (29%) had mild, 145/342 (42%) moderate, 56/342 (16%) severe, and 42/342 (12%) critical disease. The proportion of participants who reported at least 1 persistent symptom at 12 weeks after illness onset was greater in those with severe/critical disease (86.7% [95% confidence interval {CI} = 76.5-92.7%]) compared to those with mild or moderate disease (30.7% [95% CI = 21.1-40.9%] and 63.8% [95% CI = 54.8-71.5%], respectively). At 12 months after illness onset, two-fifths of participants (40.7% [95% CI = 34.2-7.1]) continued to report ≥1 symptom. Recovery was slower in female compared to male participants (adjusted hazard ratio [aHR] 0.65 [95% CI = .47-.92]) and those with a body mass index [BMI] ≥30kg/m2 compared to BMI <25kg/m2 (hazard ratio [HR] 0.62 [95% CI = .39-.97]).

Conclusions: COVID-19 symptoms persisted for one year after illness onset, even in some individuals with mild disease. Female sex and obesity were the most important determinants of speed of recovery from symptoms.

Keywords: Long COVID; recovery; symptoms.

Figure 1.

Kaplan-Meier estimates of time from illness onset to complete recovery from symptoms, by clinical severity group. Clinical severity groups of severe and critically severe COVID-19 combined due to small numbers. Dashed red vertical line denotes 12 weeks (cutoff point for post-COVID syndrome, as per NICE definition); black vertical lines indicate time-points at which participants were censored. Participants who were vaccinated while still having symptoms (n = 91, median time from onset of symptoms to vaccination 249 days [IQR 142-365]) were right-censored at date of first vaccination. Curves represent the percentages of study participants recovering from symptoms during 1 year after COVID-19 illness onset. Shaded areas represent 95% CIs. The numbers of individuals at risk during each 28-day interval since illness onset are given below the graph. Abbreviations: CI, confidence interval; COVID-19, coronavirus disease 2019; NICE, National Institute for Health and Care Excellence.

Figure 2.

Unadjusted and adjusted hazard ratios of time to complete recovery for age, sex, BMI, and number of comorbidities at illness onset. Comorbidities counted are those listed by the WHO as being associated with a higher risk of developing severe or critical COVID-19 [11, excluding BMI]. BMI categorized in kg/m² as: <25, underweight or normal weight; 25 up to 30, overweight; >30, obese. P-value calculated using likelihood ratio test. Abbreviations: aHR, adjusted hazard ratio; BMI, body mass index; CI, confidence interval; COVID-19, coronavirus disease 2019; HR, hazard ratio; WHO, World Health Organization.