A nationwide questionnaire study of post-acute symptoms and health problems after SARS-CoV-2 infection in Denmark

Participants

In this study, 430,173 individuals (40.0% test positive) were invited to complete the questionnaire. A total of 153,412 (35.7%) participants fully completed the questionnaire, 16,125 (3.7%) partially completed the questionnaire, whereas 260,637 (60.7%) individuals were non-responders. Among those, who completed the questionnaire, 532 test negatives were excluded, due to reporting having been found seropositive, leaving replies from 152,880 participants available for analysis. The questionnaires were completed approximately 6 (14.7%), 9 (69.7%), and 12 months (15.5%) after the test.

Compared to non-responders, participants who fully completed the baseline questionnaire were more often: females, born in Denmark, older (50–70 years old), more often working within healthcare, and living outside of the capital region (Supplementary Table 1).

Among the 171,992 test positives and 258,181 test negatives, who were invited to participate, response rates were very similar, 35.5% and 35.8%, respectively. The participants consisted of 93,494 females (61.2%) and 59,386 males (38.8%) with median ages 50 years (IQRs: 36, 60) and 54 years (IQRs: 41, 64), respectively (Table 1). Compared to the test negatives, test positives were more often: males, younger, students or having full-time employment, and more physically active, and less often: pensioners or smokers (Table 1).

Table 1 Characteristics of 152,880 participants tested for SARS-CoV-2, September 1, 2020–April 2, 2021.

At least one comorbidity was reported by 36.6% of participants (Supplementary Table 1).

Symptoms around the test date (acute symptoms)

Among test positives, 84.3% reported at least one acute symptom within the period lasting from 1 week before the test and until 4 weeks after the test with a median of six symptoms, compared to a median of four among test negatives with symptoms as test indication. Among all test negatives, irrespective of test indication, 13.5% reported at least one symptom around the test date with a median of two different symptoms. The most common acute symptoms among test positives were fever (55.0%), fatigue/exhaustion (47.2%) and headache (44.1%) (Supplementary Fig. 1). The largest risk differences (RD) between test positives and -negatives tested due to symptoms, were observed for dysgeusia (altered/reduced sense of taste) (RD = 34.49%, 95% CI 33.74–35.28%), dysosmia (altered/reduced sense of smell) (RD = 33.87%, CI 95% 33.06–34.73%) and fever (RD = 23.90%, 95% CI 22.35–25.28%) (Supplementary Fig. 1).

Symptoms 6–12 months after test (post-acute symptoms)

Among test positives, 29.6% reported at least one symptom 6–12 months after testing compared to 13.0% of all test negatives. In both groups, two were the median number of symptoms reported. The three most common symptoms 6–12 months after testing positive were fatigue/exhaustion (11.1%), dysosmia (10.9%), and dysgeusia (8.8%) (Fig. 1). The most marked risk differences between test positives and test negatives 6–12 months after test were for dysosmia (RD = 10.92%, 95% CI 10.68–11.21%), dysgeusia (RD = 8.68%, 95% CI 8.43–8.93%), and fatigue/exhaustion (RD = 8.43%, 95% CI 8.14–8.74%) (Fig. 1). In addition, dyspnea, reduced strength in legs/arms, sleeping legs/arms, muscle/joint pain, headache, dizziness, chest pain, reduced appetite, hot flushes/sweat, chills, fever, nausea, diarrhea, abdominal pain, and red runny eyes were all significantly more common among test positives (Fig. 1).

Fig. 1: Risk differences of symptoms after 6–12 months, comparing SARS-CoV-2 test-positive and test-negative participants.

Note: Bars indicate risk differences (center) with 95% confidence intervals (length of error bars) adjusted for age, sex, comorbidities, obesity, healthcare occupation, and time after testing (in months). For post-acute symptoms 6–12 months after the test date, all test negatives no matter the indication for testing are used as the control population. All symptom questions were mandatory, so for all lines the proportions are based on 61,002 test-positive and 91,878 test-negative individuals. An individual could only participate in the study once, as either test-positive or test negative.

New diagnoses and general health problems 6–12 months post test

At least one diagnosis of depression, anxiety, chronic fatigue symptom (CFS), fibromyalgia, or post-traumatic stress disorder (PTSD) with new onset within the first 6, 9, or 12 months after the test was reported by 7.2% of test positives, compared to 3.3% of test negatives. The most frequently reported diagnoses were chronic fatigue syndrome (4.0%), depression (3.5%), and anxiety (3.4%) (Fig. 2). All three diagnoses were more common among test positives compared to test negative with statistically significant risk differences of 2.53% (2.35–2.71%), 1.00% (95% CI 0.81–1.19%), and 1.15% (95% CI 0.95–1.34%), respectively (Fig. 2). PTSD was also marginally more common among test positives with a statistically significant risk difference of 0.16% (95% CI 0.03–0.28%).

Fig. 2: Risk differences of self-reported new diagnoses received between the test date and until 6-12 months after, comparing SARS-CoV-2 test-positive and test-negative participants.
figure 2

Note: Bars indicate risk differences (center) with 95% confidence intervals (length of error bars) adjusted for age, sex, comorbidities, obesity, healthcare occupation and time after testing (in months). PTSD = post-traumatic stress disorder. For diagnoses with onset between the test date and until 6–12 months after the test date, all test negatives no matter of the indication for testing are used as control population. All symptom questions were mandatory, so for all lines the proportions are based on 61,002 test-positive and 91,878 test-negative individuals. An individual could only participate in the study once, as either test-positive or test negative.

Among test positives, 53.1% reported at least one of the following problems with new onset within the first 6, 9, or 12 months after the test date: difficulties concentrating; memory issues; mental exhaustion; physical exhaustion or sleep problems, whereas the proportion among test negatives was 11.5%. The most common problems among test positives were physical exhaustion (RD = 40.45%, CI 95% 39.99–40.97%), mental exhaustion (RD = 32.58%, 32.11–33.09%), difficulties concentrating (RD = 28.34%, CI 95% 27.91–28.78%) and memory issues (RD = 27.25%, CI 95% 26.80–27.71%) (Fig. 3). All the aforementioned health problems were more often reported by test positives than test negatives with large risk differences (Fig. 3).

Fig. 3: Risk differences of self-reported health problems with new onset between the test date and until 6–12 months after, comparing SARS-CoV-2 test-positive and test-negative participants.
figure 3

Note: Bars indicate risk differences (center) with 95% confidence intervals (length of error bars) adjusted for age, sex, comorbidities, obesity, healthcare occupation, and time after testing (in months). For health problems with onset between the test date and until 6–12 months after the test date, all test negatives no matter of the indication for testing are used as control population. All symptom questions were mandatory, so for all lines the proportions are based on 61,002 test-positive and 91,878 test-negative individuals. An individual could only participate in the study once, as either test-positive or test negative.

Duration of individual symptoms

When looking at estimated RDs for questionnaires completed at 6, 9, or 12 months separately, RDs tended to decrease over time. Among the ten symptoms with the largest overall RDs, the estimates decreased over time for all except dysosmia and dysgeusia for which estimates were largest at 9 months (Supplementary Table 3).

Post-acute symptoms among hospitalized patients

The occurrence of post-acute symptoms among test positives hospitalized due to covid-19 (4.0%) and non-hospitalized test-positive individuals (96.0%) was compared (Supplementary Fig. 2). Considerable risk differences were observed for fatigue/exhaustion (RD = 8.64%, 95% CI 6.70–10.74%), reduced strength in arms/legs (RD = 7.13%, 95% CI 5.55–8.66%) and dyspnea (RD = 6.71%, 95% CI 5.17–8.39). The risk for all symptoms, except for dysgeusia, dysosmia, and runny nose were higher among hospitalized than non-hospitalized individuals.

Post-acute symptoms stratified by age and sex

Risk differences for symptoms 6–12 months after the test were stratified by age group and sex in order to assess the existence of subgroups at greater risk of post-acute symptoms (Fig. 4 and Supplementary Data 1). Based on descriptive results, the majority of post-acute symptoms tended to more often be reported by females and especially by 30–59-year-old participants. Stratified RDs for experiencing at least one of the symptoms: fatigue/exhaustion, dysgeusia, dysosmia, 6–12 months after test, were higher for females (RD = 18.0%, 95% CI 17.5–18.5%) compared to males (RD = 13.1%, 95% CI 12.6–13.5%). In addition, RDs for experiencing at least one of these symptoms were higher for 30–59 year olds (RD = 18.2%, 95% CI 17.7–18.7%) compared to for all other age groups (15–29 and 60 + ) (RD = 13.5%, 95% CI 13.0–13.9%).

Fig. 4: Risk differences of symptoms after 6-12 months, comparing SARS-CoV-2 test-positive and test-negative participants, stratified by sex and age group.
figure 4

Note: Risk differences (center) with 95% confidence intervals (width of error bands) were adjusted for comorbidities, obesity, healthcare occupation, and time after testing (in months).

Similar trends and more pronounced differences were observed for new onset of memory-, concentration-, or sleep problems, as well as mental or physical exhaustion (Supplementary Fig. 3 and Supplementary Data 2). Risk differences for new onset of diagnoses of anxiety were highest among 20–29-year-old females (Supplementary Fig. 4 and Supplementary Data 3). Depression were more often reported by 30–39-year-olds regardless of sex.

Sick leave

Full or part-time sick leave was more common after a SARS-CoV-2 infection. Among the test positives 12.0% reported taking any sick leave 4 weeks after the test and until filling in the questionnaire 6–12 months later, compared to 7.7% of test negative (RD = 4.32%, 95% CI 4.00–4.64%). Full-time sick leave was reported by 9.4% of test positives and 6.5% of test negative (RD = 3.20, 95% CI 2.88–3.47%), whereas part-time sick leave was reported by 4.2% of test positives compared to 1.7% of test negative (RD = 2.43%, 95% CI 2.25–2.62%). Some individuals reported both full- and part-time sick leave.