True prevalence of long-COVID in a nationwide, population cohort study – Nature.com

Overall, 345,673 questionnaires were completed by 288,173 individuals, of whom 257,341 (89%) consented to record linkage to their test result. Following linkage, 53,530 were excluded because they reported a previous positive test that was not recorded on the database, and 5,715 because they had asymptomatic infections. Of the remaining 198,096 individuals, 98,666 (49.8%) had previous symptomatic, laboratory-confirmed SARS-CoV-2 infection and 99,430 (50.2%) had never had a positive test. PCR tests took place between the 20th of April 2020 and the 31st of May 2022. Questionnaires were completed between the 10th of May 2021 and the 14th of November 2022. Compared with those who did not provide consent, participants in the final sample were more likely to be female (58.8% vs 51.8%; p-value<0.001), were older (>40 years 64.0% vs 51.1%; p-value<0.001) and slightly more deprived (most deprived SIMD quintile 20.8% vs 20.4%; p-value<0.001).

Infected individuals were less likely to have pre-existing health conditions and more likely to have been vaccinated (Table1). Because new first infections occurred over time, later periods of the pandemic were less common in the never infected group. Whilst 64.5% reported at least one symptom six months following SARS-CoV-2 infection, this was also true of 50.8% of those never infected (Table2). Results were similar at 12 (67.8% versus 55.0%) and 18 (72.6% versus 56.2%) months follow-up. The crude prevalence of at least one symptom attributable to SARS-CoV-2 infection was 13.8% (13.2%,14.3%), 12.8% (11.9%,13.6%), and 16.3% (14.4%,18.2%) at six, 12 and 18 months respectively. Following adjustment for potential confounders, these figures were 6.6% (6.3%, 6.9%), 6.5% (6.0%, 6.9%) and 10.4% (9.1%, 11.6%), respectively (Supplementary Table1). The attributable prevalence was higher in women and those who had had more vaccination doses prior to infection and lower in those with more pre-existing health conditions (Fig.1). The adjusted attributable percentage was higher for people infected later in the pandemic: 6.7% (6.2%, 7.1%) and 7.9% (6.9%, 9.0%) at six months follow-up for the delta and omicron variants respectively compared with 3.9% (3.2%, 4.6%) for the alpha variant (Supplementary Table1).

Data are presented as adjusted attributable prevalence values 95% confidence intervals. SIMD Scottish Index of Multiple Deprivation; LTC Long term condition; VOC variant of concern. N=132,879. Adjusted for age, sex, SIMD quintile, number of LTCs, ethnic group, vaccination status, and variant period. Numerical values of the estimates are provided in Supplementary Table1.

Of the 98,666 participants with previous symptomatic infection 2256 (2.29%) had severe infection. At six months follow-up the crude prevalence of at least one symptom was 64.3% following mild infection compared with 79.3% following severe infection. These values were 67.8% and 82.5%, and 71.7% and 84.0%, respectively at 12 and 18 months follow-up.

Our finding that the true prevalence of long-COVID was 6.610.3% is not inconsistent with 12.7% reported in the Netherlands4 and the WHO estimate of 1020%1. Based on these three sources, the UK Office for National Statistics estimate of 2.7% may be an underestimate. In our previous analysis of the same cohort, 48% of people self-reported that they were not fully recovered six months following symptomatic SARS-CoV-2 infection5. Similarly, meta-analysis of published studies reported that 45% had unresolved symptoms at 4 months follow-up3. However, our findings from the current study suggest that whilst 64.572.6% of people report at least one symptom six to 18 months following SARS-CoV-2 infection, only 6.6%10.3% are likely to have long-COVID. The symptoms of the remainder are likely to have occurred without SARS-CoV-2 infection but some people may mistakenly attribute them to long-COVID. Further work is required to refine the definition and diagnosis of long-COVID and support appropriate management.

A national cohort study in England used similar methodology to estimate long-COVID prevalence in adolescents aged 1117 years6. Potential participants were invited from the individuals in Public Health Englands SARS-CoV-2 testing database. Invitations to complete an online questionnaire were sent by letter, with a response rate of 13%. Those who tested positive for SARS-CoV-2 (n=3065) were matched by month of test, age, sex, and geographical region to adolescents who tested negative (n=3739). At 3 months follow-up the crude prevalence of at least one symptom attributable to infection was 13.2%, very close to our estimate in adults of 13.7% at 6 months follow-up.

Symptoms, reduced quality of life, impairment of activities of daily living, and self-reported non or partial recovery following SARS-CoV-2 infection are more common among people with pre-existing health problems, especially multimorbidity5. However, the findings of this study did not support the conclusion that their worse health following SARS-CoV-2 infection is due to a higher prevalence of long-COVID. This is based on us applying a modification of the WHO definition of long-COVID as one or more persistent or new symptom. We could not examine whether, for example, their existing symptoms deteriorated more as a result of SARS-CoV-2 infection than would otherwise have occurred. Our modification of the WHO definition does not incorporate the minimum symptom duration of at least 2 months. We could not determine if the participants reported symptoms lasted for at least this duration.

Whilst the percentage of people reporting one or more symptom at six months was slightly lower following omicron (63.3%) than the alpha (66.8%) and delta variants (66.7%), the true prevalence of long-COVID at six months was higher following omicron and delta than the alpha variant. Our adjusted result contradicts the findings of studies without comparison groups, that concluded that long-COVID is less prevalent following the omicron variant7, 8. In a Norwegian prospective cohort study, Magnusson et al. found that, compared with individuals who tested negative for SARS-CoV-2, the risk of ongoing symptoms posed by the omicron and delta variants were comparable at 14-126 days follow-up9.

Strengths of this study include its large, unselected study sample recruited from the general population, laboratory confirmation of infection status, and inclusion of a comparison group. To minimise bias, the comparison group was matched by age, sex and deprivation and we adjusted for a wide range of other confounders. Nonetheless, residual confounding is possible in any observational study and may explain the finding of a higher prevalence of long-COVID among people who had more vaccinations prior to infection. This finding conflicts with that of Antonelli et al.10, who reported reduced odds of long-duration (28 days) symptoms following two vaccine doses compared with no vaccination.

Similarly, the apparent higher prevalence of long-COVID 18 months following infection may reflect the onset of new symptoms, residual confounding due to over-representation of infections early in the pandemic in spite of adjustment for dominant variants, or be due to retention bias whereby retention is higher in those with symptoms. Both groups gain 6 months of age between questionnaires and most symptoms increase with age. Moreover, both SARS-CoV-2 infection and many of the symptoms reported at follow-up vary by season. However, this is more likely to explain differences between 6 and 12 months follow-up and between 12 and 18 months. People dying from long-COVID over time could contribute to a fall in the prevalence of long-COVID over follow-up. However, our findings do not reflect such a fall.

Selection bias may be present in those who were tested for SARS-CoV-2, those who completed the questionnaire, and those who consented to linkage. During the time period when index PCR tests were conducted testing was available to everyone free of charge. However, people might be less likely to have been tested if their symptoms were mild resulting in some bias in testing. Furthermore, selection bias in questionnaire completion could potentially lead to overestimation of associations if having ongoing symptoms made participation more likely, or alternatively underestimation of associations if having more severe ongoing symptoms affected the ability to participate. In terms of linkage consent it is difficult to determine what direction of effect this might have. Despite this limitation our methodology represents a pragmatic recruitment method that allows representative response at a population level.

The crude prevalence of long-COVID was higher following severe infection than mild infection. However, we were unable to calculate adjusted attributable prevalence stratified by infection severity. Population attributable risk is not calculable by severity because it is a detailed version of the exposure variable (test status), meaning that severity and test status are strongly correlated. Future work should explore other indicators of severity and Covid-19 history.

There is the potential for misclassification bias. Antigen tests were not available. Moreover, some individuals in the comparison group may have had SARS-CoV-2 infection that was not detected by a PCR test. This risk was reduced by excluding participants who had only negative PCR tests recorded but who self-reported that they had had SARS-CoV-2 infection. Nevertheless, the risk of classification error due to undiagnosed, asymptomatic infection remains.

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True prevalence of long-COVID in a nationwide, population cohort study - Nature.com