Multidimensional phenotyping of the post‐COVID‐19 syndrome: A Swiss survey study

Abstract Introduction Post‐COVID‐19 syndrome affects approximately 10–25% of people after a COVID‐19 infection, irrespective of initial COVID‐19 severity. The aim of this project was to assess the clinical characteristics, course, and prognosis of post‐COVID‐19 syndrome using a systematic multidimensional approach. Patients and Methods An online survey of people with suspected and confirmed COVID‐19 and post‐COVID‐19 syndrome, distributed via Swiss COVID‐19 support groups, social media, and our post‐COVID‐19 consultation, was performed. A total of 8 post‐infectious domains were assessed with 120 questions. Data were collected from October 15 to December 12, 2021, and 309 participants were included. Analysis of clinical phenomenology of post‐COVID‐19 syndrome was performed using comparative statistics. Results The three most prevalent post‐COVID‐19 symptoms in our survey cohort were fatigue (288/309, 93.2%), pain including headache (218/309, 70.6%), and sleep–wake disturbances (mainly insomnia and excessive daytime sleepiness, 145/309, 46.9%). Post‐COVID‐19 syndrome had an impact on work ability, as more than half of the respondents (168/268, 62.7%) reported an inability to work, which lasted on average 26.6 weeks (95% CI 23.5–29.6, range 1–94, n = 168). Quality of life measured by WHO‐5 Well‐being Index was overall low in respondents with post‐COVID‐19 syndrome (mean, 95% CI 9.1 [8.5–9.8], range 1–25, n = 239). Conclusion Fatigue, pain, and sleep–wake disturbances were the main symptoms of the post‐COVID‐19 syndrome in our cohort and had an impact on the quality of life and ability to work in a majority of patients. However, survey respondents reported a significant reduction in symptoms over 12 months. Post‐COVID‐19 syndrome remains a significant challenge. Further studies to characterize this syndrome and to explore therapeutic options are therefore urgently needed.


| INTRODUC TI ON
The SARS-CoV-2 pandemic including its post-infectious sequelae are a major health concern. Post-COVID-19 syndrome (also termed

or Long Haulers) is defined by the World Health
Organization (WHO) as follows: "Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis". [1] In the year 2021, 204.98 million people have been infected worldwide. [2] Not all of the infected people recover completely, as 9.9-22.1% remain symptomatic even months after the initial COVID-19 infection [3] and subsequently develop a post-COVID-19 syndrome. By extrapolation of these numbers, be- Omicron variant, which is described to have a threefold higher reproduction rate compared with the Delta variant, numbers of the post-COVID-19 syndrome might further increase. [5] Despite the large amount of affected people and even though post-infectious syndromes have been described since decades, for example, as the von Economo's syndrome being a post-encephalitis syndrome [6], our knowledge on post-infectious fatigue syndrome, in general, is still limited. Post-COVID-19 syndrome is characterized by multiple symptoms including fatigue, pain, and sleep disturbances. [7] Recent articles have unequivocally highlighted that fatigue is one of the most frequent symptoms occurring in 30-90% of the affected. [7][8][9][10][11] Fatigue is defined as a debilitating feeling of mental and/or physical loss of energy and can be accompanied especially in the post-COVID-19 syndrome by a post-exertional malaise. [12] Post-COVID-19 syndrome affects the social well-being. Studies on non-hospitalized patients with COVID-19 showed that between 12 and 23% remain absent from work even 3-7 months after COVID-19. [11] So far, it is unclear how many of them will remain unable to work and eventually need invalidity pensions. The therapy of the post-COVID-19 syndrome remains challenging. The National Institute for Health and Care Excellence (NICE) recommends selfmanagement and support, including cognitive behavioral therapy (CBT) and graded exercise therapy (GET) [13]. Furthermore, the course of post-COVID-19 syndrome is still incompletely detailed.
Davis et al. report that 65.2% persons with post-COVID-19 syndrome experienced primarily neuropsychiatric symptoms including fatigue for at least 6 months. [7] In this article, we report results from an online patient survey performed in Switzerland between October 2021 and December 2021. The survey investigated multidimensional aspects of the post-COVID-19 syndrome reported by the patients, including demographic characteristics, acute COVID-19 illness, post-COVID-19 symptoms with a special focus on fatigue and sleep disturbances, treatment strategies including vaccination, as well as psychosocial aspects. "You may participate in the study if the following apply to you:
In total, 402 anonymized responses were downloaded from the Survey Monkey server on December 12, 2021. 39 incomplete responses, defined as more than 50% missing answers, and 54 responses not fulfilling the WHO post-COVID-19 criteria due to symptom duration <3 months were removed, leading to a data set of 309 responses.

| Basic cohort characteristics
The majority of respondents to our online survey were fe-

| Phenotyping mental disturbances and social aspects in respondents with post-COVID-19 syndrome
Almost one third (91/303, 30%) of respondents complained of de-

F I G U R E 1 Study flowchart of responses downloaded from the
Survey Monkey server on December 12, 2021 *defined as more than 50% missing answers.
Post-COVID-19 syndrome also had an impact on work ability.

| Phenotyping outcome and prognosis of the post-COVID-19 syndrome
The participants retrospectively rated their symptoms over a period of 12 months. We observed a decrease in the cumulative number of In addition, the time between acute COVID-19 and completion of the questionnaire was longer in patients without confirmed infection.
(MWT, p < 0.001). There were no differences in therapeutic strategies between these two groups (Table S8).

| DISCUSS ION
This study focuses on the characteristics and disease course in participants with post-COVID-19 syndrome in Switzerland based on an online survey of patient-reported outcomes. This is the first Swiss study of its kind including all regions of Switzerland ( Figure S1). The   When assessing fatigue in our cohort, the fatigue related to the non-pharmaceutical interventions to control the spread of SARS-CoV-2 has to be considered as possible confounder [20][21][22] as they can also be associated with fatigue, which was recently recognized by the WHO and named Pandemic Fatigue. [23] However, we expect the impact on our survey to be rather low, as our survey lasted from observed. [20] Here, in agreement with previous data [21][22][23], our study also found that insomnia and excessive daytime sleepiness (EDS) are common symptoms of the post-COVID-19 syndrome Date not yet agreed 2 (4.2) 48 Abbreviations: 95% CI, 95% confidence interval; ESS, Epworth Sleepiness Scale; FSS, Fatigue Severity Score; PCR: polymerase chain reaction; WHO: World Health Organization. We have also taken into account the initial low test capacity. This was significantly increased in the 12th week of 2020 (i.e., since 8th-March-2020). [24] In our cohort, only 12/309 (3.2%) were infected before this time. We therefore do not expect a relevant bias by the national testing capacities. Little is known about the risk factors for developing a post-COVID-19 syndrome. A recent study showed that bronchial asthma is a possible risk factor. [25] In our study, 11% of the participants had bronchial asthma. This percentage is higher than the prevalence of bronchial asthma in the Swiss population which ranges from 4.5% to 6.8%. [26] Thus, this could also be an indication that bronchial asthma might contribute to the development of post-COVID-19 syndrome.
Post-COVID-19 syndrome has a relevant effect on respondents 'quality of life and ability to work. In our study, more than half of the respondents reported an inability to work, which persisted on average for almost 6 months. This is consistent with previous studies of non-hospitalized patients with COVID-19 reporting that about 12-23% remain absent from work at 3 and 7 months after acute COVID-19. [7,11] The inability to work lasts usually longer than 13 weeks [8,10], which was also found in our work. In our sur-

DATA AVA I L A B I L I T Y S TAT E M E N T
Following an open data approach, anonymized data of the cohort can be requested via the corresponding author.