Summary
Background
Patients often report various symptoms after recovery from acute COVID-19. Previous studies on post-COVID-19 condition have not corrected for the prevalence and severity of these common symptoms before COVID-19 and in populations without SARS-CoV-2 infection. We aimed to analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection.
Methods
This study is based on data collected within Lifelines, a multidisciplinary, prospective, population-based, observational cohort study examining the health and health-related behaviours of people living in the north of the Netherlands. All Lifelines participants aged 18 years or older received invitations to digital COVID-19 questionnaires. Longitudinal dynamics of 23 somatic symptoms surrounding COVID-19 diagnoses (due to SARS-CoV-2 alpha [B.1.1.7] variant or previous variants) were assessed using 24 repeated measurements between March 31, 2020, and Aug 2, 2021. Participants with COVID-19 (a positive SARS-CoV-2 test or a physician’s diagnosis of COVID-19) were matched by age, sex, and time to COVID-19-negative controls. We recorded symptom severity before and after COVID-19 in participants with COVID-19 and compared that with matched controls.
Findings
76 422 participants (mean age 53·7 years [SD 12·9], 46 329 [60·8%] were female) completed a total of 883 973 questionnaires. Of these, 4231 (5·5%) participants had COVID-19 and were matched to 8462 controls. Persistent symptoms in COVID-19-positive participants at 90–150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness. In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90–150 days after COVID-19 diagnosis or matched timepoint.
Interpretation
To our knowledge, this is the first study to report the nature and prevalence of post-COVID-19 condition, while correcting for individual symptoms present before COVID-19 and the symptom dynamics in the population without SARS-CoV-2 infection during the pandemic. Further research that distinguishes potential mechanisms driving post-COVID-19-related symptomatology is required.
Funding
ZonMw; Dutch Ministry of Health, Welfare, and Sport; Dutch Ministry of Economic Affairs; University Medical Center Groningen, University of Groningen; Provinces of Drenthe, Friesland, and Groningen.
Introduction
These long-term sequelae of COVID-19 have been described as the next public health disaster in the making, and there is an urgent need for empirical data informing on the scale and scope of the problem to support the development of an adequate health-care response.
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A systematic review examining the frequency and variety of persistent symptoms after COVID-19 reported that the median proportion of patients with at least one persistent symptom was 72·5%.
However, this estimated prevalence largely depends on the timeframe, population, and symptoms used to define post-COVID-19 condition. The timeframe used varies from 4 weeks to more than 6 months after a COVID-19 diagnosis, with 3 months being the most commonly used.
Furthermore, most studies have relied on follow-up of hospitalised patients with COVID-19.
The vast majority of people with COVID-19, however, have mild disease and are not hospitalised,
and hospitalisation itself is associated with somatic symptoms.
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Symptoms such as fatigue and headaches might be worsened during the pandemic also in people without COVID-19, for example, due to anxiety-induced stress or the combination of work and homeschooling.
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An additional complication is that some of the symptoms reported after COVID-19 might already have been present before COVID-19 and might even reflect a pre-existing susceptibility to COVID-19 itself, rather than being a consequence of SARS-CoV-2 infection.
Evidence before this study
We searched PubMed, Google Scholar, and preprint repositories from November, 2019, to February, 2022, for studies published in Dutch or English that investigated the course of post-COVID-19 condition (ie, long COVID) over time, the symptoms associated with post-COVID-19 condition, and the prevalence of post-COVID-19 condition. Furthermore, we searched for studies and policy documents from (global) public health institutes (eg, WHO) that aimed to clinically define post-COVID-19 condition. A formal systematic review was not conducted. Most previous research that assessed the prevalence and symptoms associated with post-COVID-19 condition did not include an adequate control group, and so no adjustments for the prevalence of somatic symptoms in the population without COVID-19 could be made. Additionally, we found no studies that included patients’ symptom prevalence before COVID-19 diagnosis; therefore, the previous studies were unable to assess whether somatic symptoms reported after a COVID-19 diagnosis were already present before SARS-CoV-2 infection. Most research was conducted in a clinical setting, disregarding post-COVID-19 condition in the general population. In the context of these shortcomings, a systematic review estimated that the median proportion of patients with at least one somatic symptom after COVID-19 was 72·5%.
Added value of this study
To our knowledge, this study is the first to include a control group matched for age, sex, and time, enabling us to adjust for symptom presence in the general population and changes herein due to public health measures and seasonal influences. Additionally, the repeated-measures nature of this study enabled us to assess symptom severity in patients with COVID-19 before they had SARS-CoV-2 infection. Therefore, we could assess whether symptom severity was truly increased after a COVID-19 diagnosis, or whether symptoms were a continuation of pre-existing symptoms. Our approach allowed for identification of core symptoms that define post-COVID-19 condition, as these are increased in severity 90–150 days after a COVID-19 diagnosis compared with patient’s pre-existing symptom severity.
Implications of all the available evidence
Our unique approach allows us to present the core symptoms, namely chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness, which could define post-COVID-19 condition. Additionally, we offer an improved working definition of post-COVID-19 condition and provide a reliable prevalence estimate in the general population corrected for pre-existing symptoms, and symptoms in COVID-19-negative controls. Taking into account the symptoms that increased in severity and could be attributed to COVID-19, while correcting for seasonal fluctuations and non-infectious health aspects of the pandemic on symptom dynamics, we estimated that 12·7% of patients with COVID-19 in the general population will experience persistent somatic symptoms after COVID-19. Additionally, these core symptoms have major implications for future research, as these symptoms have the highest discriminative ability to distinguish between post-COVID-19 condition and non-COVID-19-related symptoms.
We aimed to analyse the nature, prevalence, and severity of long-term symptoms related to COVID-19, while correcting for symptoms present before SARS-CoV-2 infection and controlling for the symptom dynamics in the population without infection.
Results
Table 1Characteristics of the COVID-19-positive participants
Data are mean (SD) or n (%).
Table 2Frequencies of participants who had presence of, or a substantial increase to, symptoms of at least moderate severity at 90–150 days after COVID-19 diagnosis or matched timepoint
Data are n (%). Symptoms are ordered according to their relative increase in frequency in COVID-19-positive participants compared with controls. A substantial increase in severity was defined as an increase in symptom severity of at least 1 point on the 5-point scale.
Discussion
This study shows post-COVID-19 condition might occur in about one out of eight people with COVID-19 in the general population. Core symptoms of post-COVID-19 condition include chest pain, difficulties with breathing, lump in throat, pain when breathing, painful muscles, heavy arms or legs, ageusia or anosmia, feeling hot and cold alternately, tingling extremities, and general tiredness. To our knowledge, this is the first study to provide a reliable assessment of the prevalence of post-COVID-19 condition, while correcting for individual symptoms present before SARS-CoV-2 infection and for the dynamics of symptoms reported by sex-matched and age-matched controls without infection in the same period during the pandemic. This corrected prevalence remained nearly unaltered irrespective of the use of the core symptoms versus a broader range of symptoms as a definition of post-COVID-19 condition. However, when including a broader range of symptoms, the ratio between patients with symptoms due to SARS-CoV-2 infection and those with unrelated symptoms decreased. Increased knowledge on both the nature of the core symptoms and the prevalence of post-COVID-19 condition in the general population represents a major step forward in our ability to design studies that ultimately inform an adequate health-care response to the long-term sequelae of COVID-19.
The major strengths of this study are the large sample size of COVID-19-positive participants identified in a general population cohort, as well as the multiple repeated measurements of symptom severity in the participants. This allowed for the calculation of pre-COVID-19 symptom severity in each participant. In addition, we were able to compare COVID-19-positive participants’ symptom severity with controls matched by sex and age who provided measurements at the same time period as the cases. Finally, the SCL-90 SOM subscale is a validated instrument, suitable for assessing symptoms in large-scale cohort studies. The addition of other COVID-19-related symptoms allowed for detailed insights into participants’ symptom dynamics.
Therefore, the prevalence of COVID-19 in this study might have been underestimated. Second, the assessed symptoms were included in the Lifelines COVID-19 cohort study at the beginning of the pandemic. Although at that time these symptoms were considered to be related to COVID-19, other symptoms such as cognitive symptoms (eg, brain fog) and post-exertional malaise were identified later during the pandemic as potentially relevant for a working definition of post-COVID-19 condition.
Third, as all participants in the Lifelines COVID-19 cohort study were aged 18 years or older, we could not assess paediatric post-COVID-19 condition. Fourth, the exact date of COVID-19 diagnosis was unknown; we therefore used the date of the first questionnaire in which COVID-19 positivity was indicated as date of diagnosis. This might have led to an underestimation of post-COVID-19 time. Lastly, as this study was conducted in the northern region of the Netherlands, these results might not be generalisable to other areas.
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Some studies included participants from post-COVID-19 support groups or predominantly patients who were hospitalised, leading to biased results.
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A systematic review analysed 11 studies that assessed the persistence of symptoms 90–180 days after COVID-19 in outpatients.
The sample sizes ranged from 59 to 2915 patients with COVID-19 and the number of assessed symptoms ranged from six to 21. The most prevalent symptom was fatigue (11–42% of patients), followed by dyspnoea (8–37%), painful muscles (7–24%), and ageusia or anosmia (3–24%). Thoracic pain was reported in 3–14% of patients at 90–180 days after COVID-19. Although we found similar prevalence rates for some of these symptoms, we also showed that these rates were lower when patients’ symptom severity before COVID-19 was taken into account. Additionally, we showed that the most prevalent symptoms are not the most distinctive symptoms for post-COVID-19 condition. Furthermore, many studies with clinical cohorts did not include a matched control group and were therefore unable to distinguish between effects of SARS-CoV-2 infection and those of the pandemic on symptoms.
Studies that included a control group could not distinguish between symptoms resulting from a SARS-CoV-2 infection and pre-existing symptoms. A large study that included 106 578 patients with COVID-19 and matched controls with influenza, which assessed the persistence of seven somatic symptoms at 90–180 days after diagnosis, found that somatic symptoms, such as headache, chest pain, and fatigue, were more frequently present in patients with COVID-19 than in the controls.
The study found higher prevalence rates for most assessed somatic symptoms than our study—for example, breathing difficulties occurred in 7·9% of patients with COVID-19 and chest pain occurred in 5·7%. Painful muscles was the only symptom that was less frequently reported (1·5% of patients). The difference in observed prevalence rates might be explained by the previous study only including patients with COVID-19 who sought help for their persistent symptoms from a health-care provider, and not adjusting for patients’ symptoms before COVID-19.
This conclusion is potentially stigmatising,
and the study has some limitations. First, serological assays were used to detect SARS-CoV-2 infection, but patients affected by post-COVID-19 condition might have lower antibody responses.
Second, the cross-sectional nature of the study with retrospective assessments is problematic, as persistent physical symptoms might have confounded recall of past illness and thus the belief in having been infected. Third, confounding by other viruses might have occurred, which might have caused both the belief of having been infected with SARS-CoV-2 and the persistent symptoms. Our study overcame these limitations by performing sensitivity analyses restricted to participants with a COVID-19 diagnosis based on a positive SARS-CoV-2 test and by the study’s prospective design. Nevertheless, our study cannot provide definitive information on the underlying mechanisms driving post-COVID-19-related symptoms. Therefore, additional research assessing the causes of post-COVID-19-related symptoms is required.
Our empirical analyses showed that these were among the core symptoms, but the most distinctive symptoms also included chest pain and ageusia or anosmia (considered important for the case definition by 55% and 57% of the Delphi panel, respectively). Additionally, tingling extremities were considered important by merely 39% of the experts, while 56% considered headache to be important for the case definition. Our results, however, suggest that tingling extremities is a core symptom whereas headache is not related to SARS-CoV-2 infection. These differences clearly show the importance of longitudinal cohort studies in the general population with pre-infection data and controls without infection to study the scale and scope of post-COVID-19 condition.
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Multiple explanations have been proposed for this phenomenon. First, women are thought to have a heightened sensitivity to pain compared with men, due to biological differences rooted in, among others, sex hormones and genotype.
Second, women might be more aware of bodily sensations than men, allowing for an easier and earlier perception of somatic symptoms in women than in men.
However, the female preponderance in symptom experience is not only due to differences in biology (ie, sex), but also in societal expectations of women and men (ie, gender roles).
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Feminine gender roles, for example, are thought to be associated with poorer access to health care, which might also explain health-related gender differences.
which is especially important given the risk of simple psychogenic explanations and the resulting consequences for patients.
Our results support a working definition at least based on the core symptoms, given the improved sensitivity ratio between cases and controls compared with a broader definition. These core symptoms were increased at 3–5 months after COVID-19, and are likely to limit functioning, prompt help-seeking, and have plausible underlying pathophysiological mechanisms. Nevertheless, research shows that COVID-19 might also affect brain functioning and mental health.
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Therefore, future research should not overlook mental health symptoms (eg, depression and anxiety symptoms), nor additional post-infectious symptoms that were not assessed in this study (eg, brain fog, insomnia, and post-exertional malaise). Additionally, future intersectional research should assess how ethnicity, gender, age, socioeconomic status, other social identities, and the presence of underlying chronic diseases are associated with symptom dynamics surrounding COVID-19 and risk of post-COVID-19 condition. Further research will focus on the clustering of COVID-19 symptoms in participants, and whether symptom clusters are associated with subtypes and distinct pathophysiological mechanisms underlying post-COVID-19 condition. We will also study genetic and environmental risk factors, and how post-COVID-19 condition affects (work) functioning and wellbeing. Additionally, as research suggests that vaccination before SARS-CoV-2 infection only partly mitigates the risk of long-term symptom sequelae 6 months after COVID-19,
further studies should assess the effect of SARS-CoV-2 vaccination and the timing thereof, and the effect of SARS-CoV-2 variants, on symptom dynamics in both adults and children.
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we found that about one in every eight patients are affected by persistent symptoms after COVID-19. This finding shows that post-COVID-19 condition is an urgent problem with a mounting human toll.
AVB analysed the data, conceptualised the analyses, and wrote the first version of the manuscript. SKRvZ and TCoH helped with conceptualising the analyses, interpreting the results, and critically revised the manuscript. AVB and SKRvZ accessed and verified the reported underlying data. JGMR conceived the study’s design, helped conceptualise the analyses, interpreted the results, and critically revised the manuscript. The Lifelines Corona Research Initiative collected the data.
