Persistence of somatic symptoms after COVID-19 in the Netherlands: an observational cohort
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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…
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