Long-term health impacts of COVID-19 among 242,712 adults in … – Nature.com

We show that symptomatic SARS-CoV-2 infection in England in adults is usually short-lived with most people reporting a short illness with symptom resolution within 2 weeks. However, in our study population, one in 10 people with symptomatic SARS-CoV-2 infection report symptoms for more than 4 weeks, one in 13 for more than 12 weeks (meeting the WHO definition for post COVID-19 condition (Long COVID)10), and 1 in 20 for more than 52 weeks. In our study population, 69% of those with persistent symptoms at 12 weeks still had symptoms at 52 weeks, meaning that 31% recovered within a year. We found that female sex, higher deprivation, having a pre-existing health condition, more severe symptoms at onset, and being infected when the original Wild-type variant was dominant was associated with having symptoms persisting for 12 weeks and 52 weeks. The above variables have previously been identified as risk factors for Long COVID2,7,11,12,13. We found a suggestion of lower reporting of persistent symptoms in older ages unlike another population-based study in the UK which found a positive linear association between age and Long COVID7.

The variant at the time of infection, initial severity and presence of pre-existing health conditions had the biggest impact on persistent symptoms, consistent with previous findings6,7,14,15. Compared to Wild-type, those infected when Omicron was dominant were 88% less likely to report symptoms beyond 12 weeks; this may reflect changing immunity in the population from previous exposure to the virus and vaccination. A recent case-control study conducted in the UK found lower odds of Long COVID with the Omicron versus the Delta variant, ranging from OR 02 (95% CI 02, 03) in those vaccinated >6 months prior to infection to 05 (95% CI 04, 06) in those vaccinated <3 months prior to infection16. We did not find conclusive evidence of effectiveness of vaccination against Long COVID. Vaccination reduces the severity of COVID-1917 and it may be through this indirect route that it has an impact on the risk of persistent symptoms post-infection. However, recent systematic reviews suggest that vaccination before SARS-CoV-2 infection could reduce the risk of subsequent Long COVID13,18,19.

The reporting of current symptoms was high across all groups in our study. For example, while 669%, 549% and 546% of individuals with ongoing persistent symptoms post-COVID-19 reported currently experiencing mild fatigue, difficulty thinking or concentrating and joint pains, respectively, the prevalence of these symptoms in those who never had COVID-19 was also high, at 311%, 152% and 355%. Indeed, a high level of symptom reporting was also observed for those who had recovered from COVID-19; the prevalence of mild fatigue, difficulty thinking or concentrating and joint pains in those with asymptomatic SARS-CoV-2 infection or who had recovered from COVID-19 within 4 weeks was 383%, 213% and 344%, respectively. These findings of high symptom prevalence in comparison groups have been observed elsewhere7,20,21, and could be due to higher participation in studies of people with current symptoms. Alternatively, this may reflect the timing of our survey which included months with high levels of upper-respiratory and influenza-like illness in the population. However, our data did show that the most specific persistent symptoms following COVID-19 were loss or change of sense of smell or taste, shortness of breath, severe fatigue, and difficulty thinking or concentrating, which were nine, seven, six and five times more likely, respectively, than in other participants. Of the few studies with a COVID-19-negative comparator group, one showed that COVID-19 cases had a higher likelihood of mood disorder, anxiety, and insomnia when compared to people with influenza or respiratory tract infection22. Another study found that in comparison to community controls, COVID-19 cases had a higher prevalence of symptoms at 6- and 9-months, including fatigue, sleep difficulties, hair loss, smell disorder, taste disorder, palpitations, chest pain, and headaches23.

There were substantial differences in currently reported health and well-being between individuals reporting ongoing persistent post-COVID-19 symptoms and those who had never had COVID-19 or had recovered, consistent with published evidence7,14,24. Encouragingly, those whose symptoms had resolved, even after 52 weeks, had general health and quality of life scores similar to those with no COVID-19 history or who recovered quickly. The dyspnoea and post-exertional malaise (PEM) scales were asked of everyone reporting shortness of breath (Dyspnoea 12) or fatigue, and individuals reporting persistent symptoms following COVID-19 scored higher (i.e. worse symptoms) than others, suggesting these symptoms may be more specific. A meta-analysis of 12 studies that evaluated health-related quality of life in individuals with Long COVID reported a pooled prevalence of poor quality of life (EQ5D Visual Analogue Scale - EQVAS) of 59% (95% CI 42, 75)24. Similarly, the Long-COVID in Scotland study found that symptomatic SARS-CoV-2 infection was associated with a wide range of impaired daily activities and reduced health-related quality of life7.

A strength of our study is that we have addressed some of the limitations of existing studies by having a comparison group and including people in the general population who had severe, mild, and asymptomatic SARS-CoV-2 infections. We compared contemporaneous symptom profiles of community-based adults reporting ongoing persistent symptoms post-COVID-19 versus those who have never had COVID-19 or have recovered. Our study is the largest yet to look at these questions and goes further than previous questionnaire-based studies with COVID-19 negative8 and never-infected7 controls by identifying factors associated not only with recovery (yes/no) but rate of recovery. Indeed, our findings highlight the importance of having a comparator cohort of participants who tested negative and experienced the pandemic and national lockdowns. However, we acknowledge the possibility of misclassification bias in our comparator groups as infections may have gone undetected particularly in stages of the pandemic when free universal testing was not available in the UK.

We also recognise that the subjective nature of symptoms creates the potential for reporting and recall bias. We used information regarding presence and duration of symptoms rather than whether participants described themselves as having Long COVID to reduce potential reporting bias. The data on symptoms at the time of PCR testing were retrospective which introduces the possibility of recall bias, although we have previously shown that REACT participant reports of symptom onset date closely mirrored the epidemic curve25. There is also a risk that recall bias may have differentially affected reporting of symptoms by participants infected at different times, along with other time-varying factors, such as behaviour, seasonal weather patterns and changing pandemic restrictions, knowledge and expectations26, which may account for at least part of the association between persistent symptoms and Wild-type infection. However, studies looking at individuals with confirmed infections of different SARS-CoV-2 strains also show lower risks with more recent variants27,28.

We used validated instruments to assess mental health29,30, quality of life31. dyspnoea32, and fatigue33 but recognise the limitations of self-reporting and floor and ceiling effects (i.e, if a higher percentage of individuals achieve either maximum or minimum scores). The PHQ-9 scale used is a diagnostic tool for depression. However, some of the somatic questions have been found to be strongly correlated with symptoms that are common in Long COVID, including fatigue, sleep disruption and brain fog34. As such, by using this scale we might be overestimating the level of depression. This issue was raised by Reem et al. who suggest the PHQ-235 screening criteria may be more appropriate for Long COVID as they do not include somatic items and simply require a score of 3 or more from the first two questions of PHQ-934. The percentage of participants in our study across all COVID-19 categories with a PHQ-2 score 3 was lower than the percentage with PHQ-910 and the difference was more marked in those with ongoing persistent symptoms post-COVID-19 (Supplementary Table7, Supplementary Table8).

Our questionnaire response rate was 346%; response rates in the Long-COVID in Scotland Study and a Dutch population-based cohort were 16% and 33-39%, respectively7,8. Like these studies, our participants were more likely to be female, older, of white ethnicity and from the least deprived areas compared with the general adult population. These issues might cause selection bias in our study; however, we did not observe substantial differences between those invited and those who participated in the study on the measured sociodemographic characteristics (Supplementary Table1).

A further limitation is that we do not present estimates for the population prevalence of persistent symptoms. To do so would require weighting but production of weights is far from straightforward given the composition of our sample. The probability of being in the sample was dependent upon the composition of the base population, varying response rates by sociodemographic group and across REACT-1 and REACT-2 rounds. We also oversampled participants who tested positive for SARS-CoV-2 and who reported persistent symptoms. Producing weights that take account of all these factors would involve making extensive assumptions which would likely introduce unknown biases.

In summary, our study provides timely data about the effect and implications of the pandemic on adults in England with and without ongoing persistent symptoms following COVID-19. Although COVID-19 is usually of short duration, some adults experience persistent and burdensome illness, although a sizeable proportion still recover after a prolonged period. Differences in symptoms and recovery are being further explored in an in-depth interview study with REACT participants to further understand the varying presentations and trajectories of post-COVID conditions36.

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Long-term health impacts of COVID-19 among 242,712 adults in ... - Nature.com