COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark

doi:10.1016/j.lanepe.2023.100756

. 2023 Oct 27:35:100756.

doi: 10.1016/j.lanepe.2023.100756. eCollection 2023 Dec.

COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark

Qing Shen^{1

2

3

4}, Emily E Joyce⁴, Omid V Ebrahimi^{5

6}, Maria Didriksen⁷, Anikó Lovik^{4

8}, Karen Sól Sævarsdóttir³, Ingibjörg Magnúsdóttir³, Dorte Helenius Mikkelsen^{9

10}, Anna Bára Unnarsdóttir³, Arna Hauksdóttir³, Asle Hoffart⁶, Anna K Kähler¹¹, Edda Björk Thórdardóttir^{3

12}, Elías Eythórsson¹³, Emma M Frans¹¹, Gunnar Tómasson^{3

13}, Helga Ask^{5

14}, Hrönn Hardardóttir¹³, Jóhanna Jakobsdóttir³, Kelli Lehto¹⁵, Li Lu^{16

17

14}, Ole A Andreassen^{17

18}, Patrick F Sullivan^{11

19}, Runólfur Pálsson^{13

20}, Christian Erikstrup⁷, Sisse Rye Ostrowski^{7

21}, Thomas Werge^{9

10

21

22}, Thor Aspelund^{3

23}, Ole B V Pedersen^{21

24}, Sverre Urnes Johnson^{5

6}, Fang Fang⁴, Unnur Anna Valdimarsdóttir^{3

4

25}

Affiliations

¹ Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, Tongji University School of Medicine, Shanghai, China.
² Institute for Advanced Study, Tongji University, Shanghai, China.
³ Centre of Public Health Sciences, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
⁴ Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Psychology, University of Oslo, Oslo, Norway.
⁶ Modum Bad Psychiatric Hospital and Research Center, Vikersund, Norway.
⁷ Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁸ Methodology and Statistics Unit, Institute of Psychology, Leiden University, Leiden, the Netherlands.
⁹ Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁰ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen and Aarhus, Denmark.
¹¹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹² Mental Health Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
¹³ Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
¹⁴ Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway.
¹⁵ Estonian Genome Centre, Institute of Genomics, University of Tartu, Estonia.
¹⁶ Institute of Health Management and Policy, School of Public Policy and Administration, Xi'an Jiaotong University, Xi'an, China.
¹⁷ NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁸ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹⁹ Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.
²⁰ Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
²¹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²² Lundbeck Foundation Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark.
²³ The Icelandic Heart Association, Kopavogur, Iceland.
²⁴ Department of Clinical Immunology, Zealand University Hospital, Denmark.
²⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

PMID: 38115966
PMCID: PMC10730314
DOI: 10.1016/j.lanepe.2023.100756

COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark

Qing Shen et al. Lancet Reg Health Eur. 2023.

. 2023 Oct 27:35:100756.

doi: 10.1016/j.lanepe.2023.100756. eCollection 2023 Dec.

Authors

Affiliations

¹ Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, Tongji University School of Medicine, Shanghai, China.
² Institute for Advanced Study, Tongji University, Shanghai, China.
³ Centre of Public Health Sciences, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
⁴ Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Psychology, University of Oslo, Oslo, Norway.
⁶ Modum Bad Psychiatric Hospital and Research Center, Vikersund, Norway.
⁷ Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁸ Methodology and Statistics Unit, Institute of Psychology, Leiden University, Leiden, the Netherlands.
⁹ Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark.
¹⁰ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen and Aarhus, Denmark.
¹¹ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹² Mental Health Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
¹³ Internal Medicine and Emergency Services, Landspitali-The National University Hospital of Iceland, Reykjavik, Iceland.
¹⁴ Department of Mental Disorders, Norwegian Institute of Public Health, Oslo, Norway.
¹⁵ Estonian Genome Centre, Institute of Genomics, University of Tartu, Estonia.
¹⁶ Institute of Health Management and Policy, School of Public Policy and Administration, Xi'an Jiaotong University, Xi'an, China.
¹⁷ NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
¹⁸ NORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
¹⁹ Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.
²⁰ Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
²¹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²² Lundbeck Foundation Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark.
²³ The Icelandic Heart Association, Kopavogur, Iceland.
²⁴ Department of Clinical Immunology, Zealand University Hospital, Denmark.
²⁵ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

PMID: 38115966
PMCID: PMC10730314
DOI: 10.1016/j.lanepe.2023.100756

Abstract

Background: Although the persistence of physical symptoms after SARS-CoV-2 infection is a major public health concern, evidence from large observational studies beyond one year post diagnosis remain scarce. We aimed to assess the prevalence of physical symptoms in relation to acute illness severity up to more than 2-years after diagnosis of COVID-19.

Methods: This multinational study included 64,880 adult participants from Iceland, Sweden, Denmark, and Norway with self-reported data on COVID-19 and physical symptoms from April 2020 to August 2022. We compared the prevalence of 15 physical symptoms, measured by the Patient Health Questionnaire (PHQ-15), among individuals with or without a confirmed COVID-19 diagnosis, by acute illness severity, and by time since diagnosis. We additionally assessed the change in symptoms in a subset of Swedish adults with repeated measures, before and after COVID-19 diagnosis.

Findings: During up to 27 months of follow-up, 34.5% participants (22,382/64,880) were diagnosed with COVID-19. Individuals who were diagnosed with COVID-19, compared to those not diagnosed, had an overall 37% higher prevalence of severe physical symptom burden (PHQ-15 score ≥15, adjusted prevalence ratio [PR] 1.37 [95% confidence interval [CI] 1.23-1.52]). The prevalence was associated with acute COVID-19 severity: individuals bedridden for seven days or longer presented with the highest prevalence (PR 2.25 [1.85-2.74]), while individuals never bedridden presented with similar prevalence as individuals not diagnosed with COVID-19 (PR 0.92 [0.68-1.24]). The prevalence was statistically significantly elevated among individuals diagnosed with COVID-19 for eight of the fifteen measured symptoms: shortness of breath, chest pain, dizziness, heart racing, headaches, low energy/fatigue, trouble sleeping, and back pain. The analysis of repeated measurements rendered similar results as the main analysis.

Interpretation: These data suggest an elevated prevalence of some, but not all, physical symptoms during up to more than 2 years after diagnosis of COVID-19, particularly among individuals suffering a severe acute illness, highlighting the importance of continued monitoring and alleviation of these targeted core symptoms.

Funding: This work was mainly supported by grants from NordForsk (COVIDMENT, grant number 105668 and 138929) and Horizon 2020 (CoMorMent, 847776). See Acknowledgements for further details on funding.

Keywords: COVID-19; Cohort; Long covid; Physical symptom.

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Conflict of interest statement

OAA receives support from the NordForsk (grant number 105668 COVIDMENT) and the European Union’s Horizon 2020 Research and Innovation Programme (Grant 847776; CoMorMent). OAA declares receiving grants or contracts from NIH NIMN Award (R01MH123724-01, 1R01MH124839, 1R01MH129742, 1R01MH129858-01A1), Research Council of Norway (RCN grants 223273, 296030, 300309, 324252), the South-East Norway Health Authority (grant 2017-112, 2022-073), European Union’s Horizon 2020 Research and Innovation Programme (Grant 964874 REALMENT), EEA-RO-NO-2018-0535, and KG Jebsen Stiftelsen (grants SKGJ-MED-008 and SKGJ-MED-021). OAA receives consulting fees from Biogen, Cortechs.ai and Milken. OAA gets Speaker’s honorarium from Janssen, Lundbeck and Sunovion, and has a patent on Intranasal Administration (US20160310683 A1). OAA participated in advisory board as National PI for JANSSEN trial depression, MAPS trial PTSD and BI trial schizophrenia. OAA declares having stock at Cortechs.ai. RP receives grant of Excellence, Icelandic Research Fund. RP declares to be the vice president at UEMS Section of Internal Medicine, a board member of the Icelandic Society of Internal Medicine, and is the president of the Icelandic Transplantation Society. EF received a payment for keynote lecture from Astra Zeneca. SUJ is a leader in Metacognitive Therapy Institute Norwegian Branch. FF receives support from the NordForsk (grant number 105668 and 138929 COVIDMENT) and the Horizon 2020 (Grant 847776; CoMorMent). UAV receives support from the NordForsk (grant number 105668 and 138929 COVIDMENT) and the Horizon 2020 (Grant 847776; CoMorMent). AL declares to receive Fredrik and Ingrid Thuring Foundation. OBVP receives Independent Research Fund Denmark (0214-00127B). QS declares receiving support from the Outstanding Clinical Discipline Project of Shanghai Pudong (Grant No.: PWYgy2021-02) and the Fundamental Research Funds for the Central Universities. PFS declares receiving funding from the Swedish Research Council (Vetenskapsrådet, award D0886501). PFS also receives consulting fees, participating on a data safety monitoring board or advisory board, and holds stock or stock options, from Neumora Therapeutics. All other authors declare no competing interests.

Figures

**Fig. 1**
Prevalence ratio (95% confidence interval) of severe physical symptom burden (PHQ-15 ≥15) among individuals with COVID-19 compared with individuals *NOT* diagnosed with COVID-19 in the four cohorts, and a meta-analysis (I²**43.2%)**^a.^aPrevalence ratios were adjusted for age, gender, residency, average monthly income, current smoking, BMI, pre-existing comorbidity, relationship status, habitual drinking, previous diagnosis of psychiatric disorder, and response period. Income was not available in Omtanke2020 (SE), and relationship status was not available in DBDS (DK).

**Fig. 2**
Prevalence ratio (95% confidence interval) of severe physical symptom burden (PHQ-15 ≥15) among people with COVID-19 compared with people *NOT* diagnosed with COVID-19, by illness severity (bedridden) according to time from diagnosis, a meta-analysis combining four cohorts^a.^aNumber of study subjects per group is located in Supplementary Table S3. Individuals with missing information on time since diagnosis or illness severity were excluded from this analysis (as shown in Table 1). Prevalence ratios were adjusted for age, gender, residency, average monthly income, current smoking, BMI, pre-existing comorbidity, relationship status, habitual drinking, previous diagnosis of psychiatric disorder, and response period. Income was not available in Omtanke2020 (SE), and relationship status was not available in DBDS (DK).

**Fig. 3**
**Prevalence ratio (95% confidence interval) of individual physical symptom severity among people with COVID-19 compared with those *NOT* diagnosed with COVID-19, by each physical symptom**^a. A. COVID-to-non-COVID cross-sectional comparison (all cohorts). B. Post-to-Pre COVID longitudinal comparison (Omtanke2020, N = 398). ^aPrevalence ratios were adjusted for age, gender, residency, average monthly income, current smoking, BMI, pre-existing comorbidity, relationship status, habitual drinking, previous diagnosis of psychiatric disorder, and response period. Income was not available in Omtanke2020 (SE), and relationship status was not available in DBDS (DK). Menstrual cramps were only applied to women aged <60 years. P-values were corrected for multiple testing using Bonferroni correction method. ∗Indicates corrected P-value <0.05; ∗∗<0.01; ∗∗∗<0.001.

**Fig. 4**
Prevalence ratio (95% confidence interval) of reporting *bothered a lot* to each symptom among people with COVID-19 compared with those *NOT* diagnosed with COVID-19 in C-19 Resilience, Omtanke2020 and DBDS, by illness severity (bedridden) according to time from diagnosis^a.^aPrevalence ratios were adjusted for age, gender, residency, average monthly income, current smoking, BMI, pre-existing comorbidity, relationship status, habitual drinking, previous diagnosis of psychiatric disorder, and response period. Income was not available in Omtanke2020 (SE), and relationship status was not available in DBDS (DK).

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COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark

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COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark

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