Post-acute symptoms, new onset diagnoses and health problems 6 to 12 months after SARS-CoV-2 infection: a nationwide questionnaire study in the adult Danish population
Authors: Vedel Sørensen Anna Irene , Spiliopoulos Lampros , Bager Peter , Nielsen Nete Munk , Hansen Jørgen Vinsløv , Koch Anders , Meder Inger Kristine , Ethelberg Steen , Hviid Anders 
Published: March 2022

AbstractBackgroundA considerable number of individuals infected with SARS-CoV-2 continue to experience symptoms after the acute phase. More information on duration and prevalence of these symptoms in non-hospitalized populations is needed.MethodsWe conducted a nationwide cross-sectional study including 152 880 individuals aged 15-years or older, consisting of RT-PCR confirmed SARS-CoV-2 cases between September 2020-April 2021 (N=61 002) and a corresponding test-negative control group (N=91 878). Data were collected 6, 9 or 12 months after the test using web-based questionnaires. The questionnaire covered acute and post-acute symptoms, selected diagnoses, sick leave and general health, together with demographics and life style at baseline. Risk differences (RDs) between test-positives and -negatives were reported, adjusted for age, sex, single comorbidities, Charlson comorbidity score, obesity and healthcare-occupation.FindingsSix to twelve months after the test date, the risks of 18 out of 21 physical symptoms were elevated among test-positives and one third (29.6%) of the test-positives experienced at least one physical post-acute symptom. The largest risk differences were observed for dysosmia (RD = 10.92%, 95%CI 10.68-11.21%), dysgeusia (RD=8.68%, 95%CI 8.43-8.93%), fatigue/exhaustion (RD=8.43%, 95%CI 8.14-8.74%), dyspnea (RD=4.87%, 95%CI 4.65-5.09%) and reduced strength in arms/legs (RD=4.68%, 95%CI 4.45-4.89%). More than half (53.1%) of test-positives reported at least one of the following conditions: concentration difficulties (RD=28.34%, 95%CI 27.34-28.78%), memory issues (RD=27.25%, 95%CI 26.80-27.71%), sleep problems (RD=17.27%, 95%CI 16.81-17.73%), mental (RD=32.58%, 95%CI 32.11-33.09%) or physical exhaustion (RD=40.45%, 95%CI 33.99-40.97%), compared to 11.5% of test-negatives. New diagnoses of anxiety (RD=1.15%, 95%CI 0.95-1.34%) or depression (RD=1.00%, 95%CI 0.81-1.19%) were also more common among test-positives.InterpretationAt the population-level, where the majority of test-positives (96.0%) were not hospitalized during acute infection, a considerable proportion experience post-acute symptoms and sequelae 6-12 months after infection.FundingNoneResearch in contextEvidence before the studyTo identify existing studies on the epidemiology and clinical nature of post-acute COVID-19 symptoms, we searched PubMed for articles published until January 4, 2022 using the search string (((SARS-CoV-2[Title/Abstract]) OR (COVID-19[Title/Abstract]) OR (coronavirus[Title/Abstract])) AND ((post-acute[Title/Abstract]) OR (“post acute”[Title/Abstract]) OR (“long haul*”[Title/Abstract]) OR (“long-term symptoms”[Title/Abstract]) OR (“long-term disease”[Title/Abstract]) OR (“long-term illness”[Title/Abstract]) OR (“persistent symptoms”[Title/Abstract]) OR (“persistent disease”[Title/Abstract]) OR (“persistent illness”[Title/Abstract]) OR (“prolonged symptoms”[Title/Abstract]) OR (“prolonged disease”[Title/Abstract]) OR (“prolonged illness”[Title/Abstract]))) OR (long-covid[Title/Abstract]) OR (“Post-COVID-19 syndrome”[Title/Abstract]) OR (“Post-COVID-19 condition”[Title/Abstract]) OR (“Post-COVID-19 symptoms”[Title/Abstract]). This resulted in 870 articles. When screening these, we focused on articles covering symptoms comprehensively or a broader area, e.g. mental health problems, rather than in-depth studies of symptoms within a single area, case stories or studies focusing on clinical management.A very wide range of post-acute symptoms originating from many different organ systems have been reported. This includes pulmonary, cardiovascular, hematologic, gastrointestinal, renal, endocrine, dermatologic, neurological and cognitive symptoms, as well as more general health problems, in particular fatigue.Based on two systematic reviews covering the period December 2019-March 2021, the majority of studies of persistent COVID-19 symptoms had until then been conducted among hospitalized patients and thus were not representative of the general population, where the majority will only have suffered mild or moderate disease. Since then some larger register-based studies as well as some smaller questionnaire- or interview-based studies have been conducted among non-hospitalized patients. Both types of studies offer advantages and disadvantages in relation to obtaining the full overview of long-term effects. Register-based studies are best suited for capturing more severe conditions confirmed by a trained physician and defined by diagnostic classification schemes, whereas questionnaires including self-reported symptoms are able to capture symptoms and health outcomes that do not easily confirm to disease diagnoses, but which are nevertheless critical to our understanding of the burden of post-acute symptoms.The number of sstudies of post-acute conditions among non-hospitalized patients with a follow-up time of more than 6 months is still limited. Some of the major remaining knowledge gaps regarding post-acute symptoms are: 1) What is the prevalence and variety of post-acute symptoms in the general population of infected persons, where the majority will only have suffered mild or moderate disease, 2) For how long do post-acute symptoms persist, and 3) Which subgroups of individuals, if any, are at higher risk of post-acute symptoms.Added value of this studyThe present nationwide questionnaire-study is based on a large, mainly adult study population (N=152 880), where all individuals in Denmark, who tested positive during the study period, were invited to participate along with comparable test-negative controls.Marked levels of post-acute symptoms and conditions were reported with changes in sense of smell and taste being the most frequently reported single physical symptoms. As many as half (53.1%) of the participants report having experienced general health problems in the form of either mental or physical exhaustion, sleep problems or cognitive problems, compared to 11.5% of control persons 6 to 12 months after the test. Our results suggest that a considerable proportion of the general population, who did not experience severe disease, are still affected 6 to 12 months after infection and that post-acute symptoms are more often experienced by females and middle-aged individuals.Implications of all available evidenceDiverse post-acute symptoms following infection with SARS-CoV-2 occur frequently. Even up to 12 months after the onset of infection, a considerable proportion of individuals, who did not experience severe disease, continue to experience symptoms. Post-acute symptoms are generally more often reported by females than males, whereas the influence of age remains unclear.