Methods

This study is based on data collected in Lifelines, a multidisciplinary, prospective, population-based, observational cohort study examining the health and health-related behaviors of people living in the north of the Netherlands. All Lifelines participants aged 18 and over received invitations to digital COVID-19 questionnaires. Longitudinal dynamics of 23 physical 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 August 2, 2021. Participants with COVID-19 (positive SARS-CoV-2 test or physician diagnosis of COVID-19) were matched by age, sex, and time for negative tests for COVID-19. We recorded pre- and post-COVID-19 symptom severity in participants with COVID-19 and compared it with matched controls.

Foundings

76 422 participants (mean age 53.7 years [SD 12·9]46 329 [60·8%] were women) 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 participants positive for COVID-19 at 90-150 days post-COVID-19 compared to before COVID-19 and compared to matched controls included chest pain, difficulty breathing, pain on breathing, painful muscles, weakness or odor, tingling of the extremities, lump in the throat, feeling hot and cold alternately, heavy hands or feet and general fatigue. 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-negative 19 controls had at least one of these core symptoms significantly increased to at least moderate severity at 90-150 days after the diagnosis of COVID-19 or the corresponding time point.

Interpretation

To our knowledge, this is the first study to report the nature and prevalence of the condition after COVID-19, while correcting for individual symptoms that existed before COVID-19 and the dynamics of symptoms in the population without SARS-CoV- 2 during the pandemic. Further research is needed that discerns potential mechanisms leading to symptomatology associated with COVID-19.

Financing

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

After recovery from acute COVID-19, a significant proportion of patients continue to experience symptoms of a physical, psychological or cognitive nature. 1 How and why patients took a long time with COVID-19. These long-term sequelae of COVID-19 have been described as the next public health catastrophe in progress, and there is an urgent need for empirical data to inform the scale and scope of the problem to support the development of an appropriate healthcare response.2 Response of our next national health disaster—long-term COVID.3

Crook H S-race Nowell J The young M P. Edison

Far COVID-Mechanisms, risk factors and management.Research has been hampered by a lack of consensus about the prevalence and nature of the post-COVID-19 condition. 2 Addressing our next national health disaster – long-term COVID. 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%.4

Nasserie T Hitler M Goodman SN

Assessing the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review. However, this estimated prevalence is highly dependent on the time frame, population, and symptoms used to define post-COVID-19 status. The time frame used varies from 4 weeks to more than 6 months after the diagnosis of COVID-19, with 3 months being the most commonly used. In addition, most studies were based on follow-up of hospitalized patients with COVID-19.4

Nasserie T Hitler M Goodman SN

Assessing the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review. The vast majority of people with COVID-19, however, have mild disease and are not hospitalized,6

The ball is OFF Oertelt-Prigione S old Hartman TC et al.

Sex- and gender-related differences in COVID-19 diagnoses and SARS-CoV-2 testing practices during the first wave of the pandemic: the Dutch Lifelines COVID-19 cohort study. and hospitalization itself is associated with physical symptoms.7 High-dimensional characterization of post-acute sequelae of COVID-19.Another complicating factor is that there is no consensus on the nature of symptoms attributable to COVID-19. Symptom selection is crucial to charting the scale and scope of the post-COVID-19 situation. However, commonly reported symptoms following COVID-19 are also common in the general population.4

Nasserie T Hitler M Goodman SN

Assessing the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review.8

Fernandez-de-Las-Peñas C Palacios-Ceña D Gomez-Butler B Square ML Florence LL

Defining post-disease symptoms (post-acute COVID, prolonged COVID, persistent post-COVID): a comprehensive classification.9

Acevedo-Mesa A The shopkeeper JN Rust A Rosmalen JGM Stomata R

Improving the measurement of functional physical symptoms with item response theory. Symptoms such as fatigue and headaches may worsen during the pandemic and in people without COVID-19, for example, due to stress caused by stress or the combination of work and education at home.10

Bekhuis E Schoevers RA there is Borkulo CD Rosmalen JG Boschloo L

The network structure of major depressive disorder, generalized anxiety disorder, and somatic symptomatology.11

Janssens KAM Rosmalen JGM Ormel J van Oort FV Oldehinkel AJ

Anxiety and depression are risk factors and not consequences of functional physical symptoms in a general adolescent population: the TRAILS study. An additional complication is that some of the symptoms reported after COVID-19 may have already been present before COVID-19 and may even reflect a pre-existing susceptibility to COVID-19 itself, rather than being a consequence of SARS infection -CoV-2.Research in context Evidence prior to 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 the post-COVID-19 condition (ie, long COVID) over time , the symptoms associated with post-COVID-19 and the prevalence of post-COVID-19. In addition, we searched for studies and policy documents from (global) public health institutes (e.g. WHO) that aimed to clinically define the situation after COVID-19. No formal systematic review was conducted. Most previous research that assessed the prevalence and symptoms associated with the post-COVID-19 condition did not include an adequate control group and thus adjustments could not be made for the prevalence of physical symptoms in the non-COVID-19 population. In addition, we found no studies that included the prevalence of patients’ symptoms prior to the diagnosis of COVID-19. Therefore, previous studies were unable to assess whether the physical symptoms reported after the diagnosis of COVID-19 were already present before SARS-CoV-2 infection. Most research has been conducted in a clinical setting, ignoring the post-COVID-19 situation in the general population. In the context of these shortcomings, a systematic review estimated that the median proportion of patients with at least one physical symptom after COVID-19 was 72.5%. Added value of this study To our knowledge, this study is the first to include an age-, sex-, and time-matched control group, allowing us to adjust for the presence of symptoms in the general population and changes in the present due to public health measures and seasonal effects. In addition, the repeated measures nature of this study allowed us to assess the severity of symptoms in patients with COVID-19 before they developed SARS-CoV-2 infection. Therefore, we could assess whether the severity of symptoms was truly increased after the diagnosis of COVID-19 or whether the symptoms were a continuation of pre-existing symptoms. Our approach allowed us to identify the key symptoms that define the post-COVID-19 state, as these are increased in severity 90–150 days after the diagnosis of COVID-19 compared to the pre-existing severity of the patient’s symptoms. Consequences of all available evidence Our unique approach allows us to present the core symptoms, i.e. chest pain, breathing difficulties, pain when breathing, muscle aches, weakness or odor, tingling extremities, throat swelling, alternating hot and cold, heavy hands or legs and general fatigue, which could define the post-COVID-19 situation. In addition, we offer an improved operational definition of the post-COVID-19 condition and provide a reliable estimate of prevalence in the general population, corrected for pre-existing symptoms and symptoms in controls who are negative for COVID-19. Taking into account symptoms that increased in severity that could be attributed to COVID-19, while correcting for seasonal variations and non-infectious health aspects of the pandemic in symptom dynamics, we estimated that 12.7% of patients with COVID-19 in the general population will experience persistent physical symptoms after COVID-19. In addition, these key symptoms have significant implications…