Long-term health impacts of COVID-19 among 242,712 adults in England

The COVID-19 pandemic has had a significant and lasting impact on global health and well-being. Beyond the immediate risks of hospitalization and death, a considerable number of individuals experience prolonged illness, often referred to as Long COVID or post-COVID-19 condition. Estimates of symptom persistence vary widely across studies, likely due to differences in study designs, populations, follow-up periods, and symptom definitions. Existing studies often suffer from small sample sizes, unrepresentative populations, and low response rates, limiting the generalizability of their findings. This large-scale study, utilizing data from the REal-time Assessment of Community Transmission (REACT) program, aims to provide a more comprehensive understanding of the long-term health consequences of COVID-19 in the English adult population. The REACT program, one of the world's largest coronavirus monitoring studies, allows for a robust comparison between individuals with persistent symptoms, those who have recovered, and those who have never been infected. This study specifically investigates the duration of symptoms in individuals with a history of symptomatic infection, identifies factors associated with symptom persistence beyond 12 weeks, and compares current self-reported health and quality of life across different groups. The large sample size and the inclusion of a negative control group strengthen the study's ability to provide reliable population-level estimates and insights into the long-term impact of COVID-19.

Several studies have explored the prevalence and characteristics of Long COVID. A meta-analysis of 194 studies estimated a pooled prevalence of persistent symptoms at 52.6% among hospitalized COVID-19 patients and 34.5% among non-hospitalized patients at a mean follow-up of 126 days. Common persistent symptoms included fatigue, pain, sleep impairment, breathlessness, and impaired activity. However, limitations in sample size, representation, and response rates in these studies highlight the need for larger, more representative studies. Initial estimates from the REACT-2 study suggested that 21.6% of adults with prior infection experienced symptoms 12 weeks post-infection, but lacked a negative control group. The Long-COVID in Scotland study found that 8% of symptomatic participants hadn't recovered by 6 or 12 months, with previous symptomatic infection strongly associated with persistent symptoms. A Dutch study identified chest pain, breathing difficulties, and general tiredness as core Long COVID symptoms. This existing literature, while informative, lacks the scale and comprehensive nature of the current study to provide robust, population-level insights into the long-term effects of COVID-19.

This study leverages data from a follow-up survey of participants in the REACT program, which comprises two large-scale studies: REACT-1 (using RT-PCR tests) and REACT-2 (using IgG antibody tests). The study aimed for a sample size of at least 160,000 participants, inviting 800,000 adults aged ≥18 years from the REACT-1 and REACT-2 participant pool who had consented to re-contact and data linkage. Over-sampling was conducted for individuals with a history of self-reported or test-confirmed COVID-19 and persistent symptoms (≥12 weeks). Participants completed an online questionnaire assessing current health, well-being, functionality, and recent symptoms. Data on COVID-19 history (PCR and LFD test results) was obtained through linkage to UK Health Security Agency (UKHSA) records, and vaccination data was linked to NHS records. The questionnaire included validated instruments for assessing mental health (GAD-7, PHQ-9), quality of life (EQ-5D-5L), dyspnoea (Dyspnoea-12), and fatigue (PEM items from DePaul Symptom Questionnaire). Statistical analyses included logistic regression (to assess associations between factors and symptom persistence), Kaplan-Meier survival curves (to visualize time to symptom resolution), and accelerated failure time models (to assess factors associated with the rate of recovery). The study categorized participants based on their COVID-19 history (no COVID, asymptomatic/resolved short COVID, resolved short COVID, resolved persistent COVID, ongoing persistent COVID). Only symptomatic SARS-CoV-2 infections confirmed by positive tests were included. Participants with less than 12 weeks of follow-up from their COVID-19 episode were excluded. Index of Multiple Deprivation (IMD) 2019 was used to measure deprivation. Data were analyzed using STATA version 15.0.

Of 800,000 invited participants, 276,840 (34.6%) completed the questionnaire. 157,668 (59.1%) had tested positive for SARS-CoV-2. Among 130,251 participants with symptomatic COVID-19, the median duration of symptoms was 1.3 weeks (IQR 6 days to 2 weeks). 10.2%, 7.5%, and 5.2% reported ongoing symptoms beyond 4, 12, and 52 weeks respectively. Factors associated with symptoms lasting ≥12 weeks and ≥52 weeks (Long COVID and very Long COVID) included female sex (aOR 1.42 and 1.49 respectively), ≥1 comorbidity (aOR 1.31 and 1.52 for 1 comorbidity, and 1.46 and 2.35 for ≥2 comorbidities), and moderate or severe initial symptoms (aOR 1.76 and 4.87 for severe symptoms respectively). The odds of Long COVID were lower in those infected during periods when Alpha, Delta, and Omicron variants were dominant compared to the Wild-type. In those with Long COVID, longer recovery times were associated with female sex and comorbidities. Shorter recovery times were associated with other/mixed ethnicity, lower deprivation, non-current smoking, and infection during later variants. The most common symptoms among those with persistent symptoms were mild fatigue (66.9%), difficulty thinking (54.9%), and joint pains (54.6%). However, these were also common in comparison groups. Significant differences were observed in loss/change of smell/taste, shortness of breath, severe fatigue, and difficulty concentrating, which were substantially more prevalent in those with persistent symptoms. Participants with ongoing symptoms lasting ≥12 weeks reported worse health, more symptoms, reduced daily activity, more post-exertional malaise, and worse mental health and quality of life. Those who recovered from Long COVID (even after 52 weeks) had health statuses similar to those who never had COVID-19 or recovered quickly.

This study's large sample size and inclusion of a negative control group provide robust evidence of the significant long-term health impacts of COVID-19 in the English adult population. The findings confirm that while many COVID-19 infections are self-limiting, a considerable proportion of individuals experience persistent symptoms for many weeks or months, impacting their mental and physical health and quality of life. The identification of key risk factors, including sex, comorbidities, initial symptom severity, and the variant at the time of infection, is crucial for targeted interventions and support. The observed lower risk of Long COVID associated with more recent variants may be attributed to factors like increased population immunity from prior infection and vaccination, although the study didn't find conclusive evidence of vaccination effectiveness against Long COVID. The high prevalence of certain symptoms in comparison groups highlights the complexity of symptom attribution and underscores the importance of considering other contributing factors and using specific symptoms to define Long COVID. The study's findings emphasize the need for ongoing monitoring, support for individuals with Long COVID, and further research to understand the mechanisms of persistent symptoms and develop effective treatments. The study's strengths, such as its size and comparison group, offset the limitations of self-reported data and potential recall bias, offering valuable population-level insights.

This large-scale study provides compelling evidence of the substantial and prolonged health consequences of COVID-19 in a significant portion of the English adult population. While the majority experience a short-lived illness, a considerable number develop persistent symptoms impacting their mental and physical well-being. Risk factors identified can guide targeted support and future research directions should focus on understanding the pathophysiological mechanisms underlying persistent symptoms and developing effective preventative and therapeutic strategies. Future research could also investigate the long-term effects beyond 52 weeks and explore the long-term effectiveness of vaccination in mitigating Long COVID risk.

The study's reliance on self-reported data introduces the potential for recall bias and subjective symptom reporting. The 34.6% response rate may also introduce selection bias, although the sociodemographic characteristics of participants were largely similar to those invited. The study does not provide population prevalence estimates due to complex weighting challenges, limiting the extrapolation of findings directly to the general population. Further, the retrospective nature of data collection for some variables (symptom onset and resolution) could impact accuracy. Finally, the study did not directly assess the impact of vaccination against Long COVID, although this was discussed in the context of pre-existing immunity.