Two years into the COVID-19 pandemic, many questions remain regarding patients with prolonged symptoms after SARS-CoV-2 infection. Although several studies have described post COVID-19 complications and symptoms in different settings and populations (Ayoubkhani et al., 2021, Blomberg et al., 2021, Havervall et al., 2021, Tran et al., 2022, Westerlind et al., 2021), it is difficult to compare results and draw conclusions due to the substantial heterogeneity between studies (Michelen et al., 2021). Discriminating between post-COVID-19 complications, prolonged symptoms of the acute COVID-19 infection, or consequences of possible hospital care, including post-intensive care syndrome (Rawal et al., 2017), can be difficult as the clinical presentations may overlap. Furthermore, the terminology of the condition still varies and a widely accepted definition has been lacking (Centers for Disease Control and Prevention, 2021b, National Institute for Health and Care Excellence, 2020). The World Health Organization (WHO) recently produced a consensus clinical case definition based on a Delphi process. The term "post-COVID-19 condition" (PCC) was defined as a condition that "occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually three months from the onset, with symptoms that last for at least two months and cannot be explained by an alternative diagnosis" (Soriano et al., 2022). Similarly to acute COVID-19, the symptoms and severity of PCC vary widely among affected individuals and can involve multiple organ systems (Crook et al., 2021). PCC can be used to describe the various complications arising from the acute infection, as well as a condition characterised by post-viral fatigue. Commonly reported symptoms of PCC include fatigue, dyspnoea, cognitive impairment, headache, muscle pain, and cardiac abnormalities such as chest pain and palpitations (Crook et al., 2021, Groff et al., 2021, National Institute for Health and Care Excellence, 2020, Soriano et al., 2022). The underlying processes of PCC are not fully understood, but various mechanisms for the different symptoms have been proposed, including virus-specific pathophysiologic changes, damage from the inflammatory response to the acute infection, expected sequelae of post-critical illness (Nalbandian et al., 2021), and neuroinflammatory responses in the brain (Eden et al., 2022, Kanberg et al., 2021, Song et al., 2021). The condition has been reported in patients previously hospitalised for acute COVID-19 as well as in patients with mild acute disease (Augustin et al., 2021, Ayoubkhani et al., 2021). Several studies have described PCC as more common in females than males (Augustin et al., 2021, Huang C. et al., 2021) and the condition does not seem to be restricted to the elderly (Ayoubkhani et al., 2021, Daugherty et al., 2021).
In September 2020, just over a year before the Delphi consensus definition was released, the WHO introduced the PCC diagnosis code (U09.9) within the International Classification of Disease revision 10 (ICD-10), and it was quickly adopted in the Swedish version (World Health Organization, 2020a, 2020b). However, some countries including the UK are instead using the emergency code U07.4 (NHS Digital, 2021) and it was not until October 2021 that the code U09.9 was introduced in the US (Centers for Disease Control and Prevention, 2021a). In Sweden, the PCC diagnosis code U09.9 was implemented comparatively early and has been in use since 16 October 2020 (National Board of Health and Welfare, 2021). The Swedish National Board of Health and Welfare recommends using the PCC diagnosis code to describe a symptom or condition that a physician assesses to be caused by a previous COVID-19 infection. The recommendations do not specify how soon after the acute infection the PCC diagnosis should be applied.
In the present study, we utilised Swedish hospital data and primary healthcare data from the two largest regions in Sweden (Region Stockholm and Region Västra Götaland, 2.4 and 1.7 million inhabitants, respectively (Statistics Sweden, 2022)) to present the incidence rate and cumulative incidence of PCC overall and in different subgroups of COVID-19 patients, and to describe the characteristics of all adult COVID-19 patients with or without a PCC-diagnosis during the first 16 months of usage of the ICD-10 diagnosis code U09.9 in Sweden.
In the present study, we utilised Swedish hospital data and primary healthcare data from the two largest regions in Sweden (4.1 million inhabitants) to present the incidence rate, cumulative incidence, and describe characteristics of all adult patients receiving a PCC diagnosis during the first 16 months of usage of the ICD-10 diagnosis code U09.9 in Sweden. We show that 10,196 individuals, 2.0 % of all COVID-19 cases, had been diagnosed with PCC during the first 16 months of usage of the PCC diagnosis code. While the overall cumulative incidence was higher in patients with severe and critical COVID-19, most of the individuals diagnosed with PCC had not been hospitalised for COVID-19. This non-hospitalised group were more likely female, older, had tertiary education, and had a previous respiratory or cardiovascular disease compared to the COVID-19 patients without PCC.
A recent systematic review reported a range of PCC prevalence from 9% to 81% among 31 studies globally reporting PCC in widely varying selected COVID-19 study populations (Chen et al., 2022), and a recent umbrella review showed prevalences between 2% and 53% among different selected populations (Nittas et al., 2022). The differences in prevalence between studies seem to a large extent be due to differences in the study populations, follow-up time, the definition of post-COVID-19 condition (one or more symptoms after a certain amount of days after COVID-19), the accuracy of diagnosis, the reporting systems, and the capacity of healthcare systems (Crook et al., 2021). For example, a survey carried out by the Office for National Statistics in the UK showed that 9.9% of patients with COVID-19 reported at least one symptom 12 weeks after the COVID-19 index date (The Office for National Statistics, 2020). A cohort study from Wuhan (n=1,276), which interviewed patients about their symptoms and conducted physical examinations, laboratory tests, and a 6-minute walking test after 6 and 12 months found that 49% of patients who previously had been hospitalised due to COVID-19 had at least one sequelae symptom 12 months after the initial infection (Huang L. et al., 2021). Assessment of PCC prevalence in truly population-based settings is rare in the previously published studies.
Since Sweden was early in implementing the U09.9 code, we chose to use this diagnosis code to describe the PCC prevalence as a reflection of actual clinical care and diagnosis-setting. There are however limitations to using U09.9 as a definition of PCC. In the Swedish National Board of Health and Welfare guidance, physicians are recommended to utilise the PCC code U09.9 when a symptom or condition is regarded as being caused by a previous COVID-19 infection. However, no instruction is given regarding how soon after the primary infection the code can be used. According to the case definition recently created by the WHO, PCC could be considered the first three months from COVID-19 onset, but four weeks have also been used as a definition in earlier studies (Wanga et al., 2021). Therefore, in our main analyses we did not define 1,578 patients as PCC cases since they were only given the PCC code within 28 days after the COVID-19 index date (and not again). Possible explanations for a PCC diagnosis within 28 days of COVID-19 index date include patients not getting tested for SARS-CoV-2 during the acute infection and then receiving a late COVID-19 diagnosis when seeking healthcare for PCC symptoms (early during the pandemic the testing capacity in Sweden was very low), or misclassification as there was no specification in Sweden on how soon after COVID-19 a PCC diagnosis could be used, or that acute COVID-19 symptoms were misclassified as PCC. It is also difficult to distinguish between PCC and other possible effects of hospitalisation and intensive care treatment. This issue is not overcome by using the U09.9 code, and we are therefore unable to discriminate between these conditions in our study. Furthermore, partly due to the wide definition of PCC and the lack of knowledge about the condition, it is likely that not all patients experiencing post-COVID-19 complications are diagnosed with PCC and receive the U09.9 code (Walker et al., 2021). In Sweden, the Public Health Agency recommended the same public health surveillance for COVID-19 in all regions, although a recent report concluded that Region Stockholm and Västra Götaland had lower test capacity than other regions, especially during 2020 (Almgren and Björk, 2021). Lastly, the diagnosis code has not yet been validated in a Swedish setting. Therefore, the true cumulative incidence of PCC could both be higher and lower than our estimate. Increased usage of the WHO-implemented ICD-10 code U09.9 in future studies can hopefully assist in making comparisons between studies, even though many complicating factors will remain.
When considering prevalence data on PCC in different settings and populations, it is important to be aware of the limitations present in the various reports. The Swedish National Board of Health and Welfare regularly presents nationwide data on the PCC prevalence in Sweden, although their results are based on aggregated primary healthcare data. Their latest report estimated that 16,019 individuals received a PCC diagnosis within the public primary healthcare from October 2020 until October 2021 in the whole of Sweden (National Board of Health and Welfare, 2022). Additionally, in the report, data from the NPR showed that 5,710 individuals received a PCC diagnosis in a hospital or outpatient clinic during the same period (National Board of Health and Welfare, 2022). However, the use of aggregated primary healthcare data, thus not individual-level data, makes it likely that there is some overlap between data from primary care and hospital/outpatient care. Furthermore, data are gathered from primary care within the public health system only, while numbers regarding private primary care are based on estimates. By having access to individual data from NPR as well as from both public and private primary healthcare, our results regarding the cumulative incidence of PCC in the two largest regions in Sweden are likely more accurate than the Swedish governmental reports. The fact that the majority of PCC patients in our study were diagnosed within primary healthcare (88.6%), further emphasises the importance of having individual-based data from primary healthcare.
Our results showed a clear difference in cumulative incidence of PCC depending on the severity of the primary infection. Among patients having required intensive care for COVID-19, 36.9 % went on to receive a PCC diagnosis, while the proportion of PCC diagnoses among non-hospitalised patients was only 1.5%. This is in line with previous reports showing a possible association between more severe acute infection and increased risk of developing PCC (Huang L. et al., 2021, Sudre et al., 2021). Furthermore, the high numbers of PCC among patients requiring intensive care for COVID-19 likely include patients suffering the consequences of hospital care, including the so-called post-intensive care syndrome (Rawal et al., 2017). Consistent with previous reports (Augustin et al., 2021, Huang C. et al., 2021, National Board of Health and Welfare, 2022), we also showed that females were more likely to receive a PCC diagnosis than men: 2.3% and 1.6%, respectively. There was also a difference across age groups, and the highest proportions of PCC were seen at ages 55-64 years. Different health-seeking behaviours between the sexes as well as between different age groups might explain some of these differences in PCC prevalence, both in terms of getting tested for SARS-CoV-2 during the initial infection and in seeking healthcare when experiencing symptoms of PCC (Thompson et al., 2016). Furthermore, patients initially hospitalised for COVID-19 might be more prone to continue seeking medical care after hospitalisation, and there might also be different patterns of health-seeking behaviour in the other subgroups evaluated in this study. One inevitable limitation to diagnosis-based register studies such as the present study is that these types of health-seeking behaviour differences across subgroups might introduce self-selection bias. Nevertheless, the results presented here will be relevant and useful for assessing the future impact of PCC on healthcare, as a reflection of real-world healthcare practices.
It is still unclear whether different SARS-CoV-2 variants have the same potential to cause sequelae symptoms and PCC after the initial infection and if there are any virus variant-specific characterisations of the condition. The present study shows that the cumulative incidence was lower in the Delta VOC period compared to the other periods, but the incidence rate was higher. This might be due to the shorter follow-up in the Delta VOC period and considering that the study end date was 15 February 2022 and that we required a minimum follow-up of 114 days, individuals whose COVID-19 index date was closer to the end of the study had less time to develop PCC. Hence, the results regarding PCC among patients infected by SARS-CoV-2 when the delta VOC was dominant (n=363) in Sweden (July 2021 until December 2021) must be interpreted cautiously. When accounting for differences in length of follow-up by using a truncated follow-up, we show that the Alpha VOC period had a higher incidence rate and cumulative incidence compared to the other two periods. PCR confirmation of COVID-19 (84.6%) was comparatively low early in the period when a mix of virus strains was circulating, due to the limited test capacity in Sweden during the first months of the pandemic.
Early in the pandemic, Sweden chose an approach to mitigate the pandemic that was different from most other countries, including the Nordic countries. The strategy was based on voluntary measures and personal responsibility of the Swedish population (Ludvigsson, 2022). A commission concluded in 2022 that although the overall mortality (2020-2021) was lower than in many other countries, earlier and more extensive measures should have been undertaken early on during the pandemic (Ludvigsson, 2022). Vaccination of individuals in risk groups started in late 2020 and early 2021 and continued on a large scale for the whole adult population in the second quarter of 2021 (Public Health Agency, 2022b). In the middle of the summer 2021, around 70% of the population had taken their first dose, meaning that the risk of severe COVID-19 had changed by the end of the study period.
Our study has several strengths: it is population-based and includes a near-complete data set from inpatient, outpatient, and primary healthcare data. Moreover, we use individual-level data and can thus distinguish individuals appearing in more than one register and avoid data duplication or overlap. Importantly, we include data from both public and private primary healthcare.
In conclusion, we present data on the estimated cumulative incidence of PCC in a truly population-based setting in the two largest regions in Sweden, together with a detailed characterisation of the patient population diagnosed with PCC during the first 16 months of usage of the ICD-10 diagnosis code U09.9. This knowledge is important to further the understanding of this emerging patient group. However, more research is urgently needed to improve diagnosis and clinical care for these patients.
Almgren M, Björk J. Kartläggning av skillnader i regionernas insatser för provtagning och smittspårning under coronapandemin; 2021. Available from: https://coronakommissionen.com/wp-content/uploads/2021/10/underlagsrapport-m-almgren-kartlaggning-av-skillnader-i-regionernas-insatser-for-provtagning-och-smittsparning-under-coronapandemin.pdf. [Accessed 01 September 2022.
Augustin M, Schommers P, Stecher M, Dewald F, Gieselmann L, Gruell H, et al. Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study. Lancet Reg Health Eur 2021;6:100122.
Ayoubkhani D, Khunti K, Nafilyan V, Maddox T, Humberstone B, Diamond I, et al. Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study. BMJ 2021;372:n693.
Blomberg B, Mohn KG, Brokstad KA, Zhou F, Linchausen DW, Hansen BA, et al. Long COVID in a prospective cohort of home-isolated patients. Nat Med 2021;27(9):1607-13.
Centers for Disease Control and Prevention. New ICD-10-CM code for Post-COVID Conditions, following the 2019 Novel Coronavirus (COVID-19). Effective: October 1, 2021; 2021a. Available from: https://www.cdc.gov/nchs/data/icd/announcement-new-icd-code-for-post-covid-condition-april-2022-final.pdf. [Accessed 28 June 2022.
Centers for Disease Control and Prevention. Post-COVID Conditions: Information for Healthcare Providers; 2021b. Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fhcp%2Fclinical-care%2Flate-sequelae.html. [Accessed 28 June 2022.
Chen C, Haupert SR, Zimmermann L, Shi X, Fritsche LG, Mukherjee B. Global Prevalence of Post COVID-19 Condition or Long COVID: A Meta-Analysis and Systematic Review. J Infect Dis 2022.
Crook H, Raza S, Nowell J, Young M, Edison P. Long covid-mechanisms, risk factors, and management. BMJ 2021;374:n1648.
Daugherty SE, Guo Y, Heath K, Dasmarinas MC, Jubilo KG, Samranvedhya J, et al. Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study. BMJ 2021;373:n1098.
Eden A, Grahn A, Bremell D, Aghvanyan A, Bathala P, Fuchs D, et al. Viral Antigen and Inflammatory Biomarkers in Cerebrospinal Fluid in Patients With COVID-19 Infection and Neurologic Symptoms Compared With Control Participants Without Infection or Neurologic Symptoms. JAMA Netw Open 2022;5(5):e2213253.
Groff D, Sun A, Ssentongo AE, Ba DM, Parsons N, Poudel GR, et al. Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection: A Systematic Review. JAMA Netw Open 2021;4(10):e2128568.
Havervall S, Rosell A, Phillipson M, Mangsbo SM, Nilsson P, Hober S, et al. Symptoms and Functional Impairment Assessed 8 Months After Mild COVID-19 Among Health Care Workers. JAMA 2021;325(19):2015-6.
Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet 2021;397(10270):220-32.
Huang L, Yao Q, Gu X, Wang Q, Ren L, Wang Y, et al. 1-year outcomes in hospital survivors with COVID-19: a longitudinal cohort study. Lancet 2021;398(10302):747-58.
Kanberg N, Simren J, Eden A, Andersson LM, Nilsson S, Ashton NJ, et al. Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up. EBioMedicine 2021;70:103512.
Ludvigsson JF. How Sweden approached the COVID-19 pandemic: summary and commentary on the national commission inquiry. Acta Paediatr 2022.
Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, Ekbom A. The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research. Eur J Epidemiol 2009;24(11):659-67.
Michelen M, Manoharan L, Elkheir N, Cheng V, Dagens A, Hastie C, et al. Characterising long COVID: a living systematic review. BMJ Glob Health 2021;6(9).
Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med 2021;27(4):601-15.
National Board of Health and Welfare. Statistik om tillstånd efter covid-19 i primärvård och specialiserad vård. 2021.
National Board of Health and Welfare. Statistik om postcovid i primärvård och specialiserad vård. 2022.
National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. NICE guideline [NG188]. 2020.
NHS Digital. COVID-19 and ICD-10; 2021. Available from: https://hscic.kahootz.com/t_c_home/view?objectId=19099248:. [Accessed 25 May 2022.
Nittas V, Gao M, West EA, Ballouz T, Menges D, Wulf Hanson S, et al. Long COVID Through a Public Health Lens: An Umbrella Review. Public Health Rev 2022;43:1604501.
Nyberg F, Franzen S, Lindh M, Vanfleteren L, Hammar N, Wettermark B, et al. Swedish Covid-19 Investigation for Future Insights - A Population Epidemiology Approach Using Register Linkage (SCIFI-PEARL). Clin Epidemiol 2021;13:649-59.
Public Health Agency. Statistik om SARS-CoV-2 virusvarianter av särskild betydelse; 2022a. Available from: https://www.folkhalsomyndigheten.se/smittskydd-beredskap/utbrott/aktuella-utbrott/covid-19/statistik-och-analyser/sars-cov-2-virusvarianter-av-sarskild-betydelse/.
Public Health Agency. Vaccinationer mot covid-19 i Sverige; 2022b. Available from: https://experience.arcgis.com/experience/6df5491d566a44368fc721726c274301. [Accessed 01 September 2022.
Rawal G, Yadav S, Kumar R. Post-intensive Care Syndrome: an Overview. J Transl Int Med 2017;5(2):90-2.
Song WJ, Hui CKM, Hull JH, Birring SS, McGarvey L, Mazzone SB, et al. Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses. Lancet Respir Med 2021;9(5):533-44.
Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV, Condition WHOCCDWGoP-C-. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis 2022;22(4):e102-e7.
Statistics Sweden. Folkmängd i riket, län och kommuner 31 december 2021 och befolkningsförändringar 2021; 2022. Available from: https://www.scb.se/hitta-statistik/statistik-efter-amne/befolkning/befolkningens-sammansattning/befolkningsstatistik/pong/tabell-och-diagram/helarsstatistik–kommun-lan-och-riket/folkmangd-i-riket-lan-och-kommuner-31-december-2021-och-befolkningsforandringar-2021/. [Accessed 28 June 2022.
Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, et al. Attributes and predictors of long COVID. Nat Med 2021;27(4):626-31.
The Office for National Statistics. The prevalence of long COVID symptoms and COVID-19 complications; 2020. Available from: https://www.ons.gov.uk/news/statementsandletters/theprevalenceoflongcovidsymptomsandcovid19complications. [Accessed 28 June 2022.
Thompson AE, Anisimowicz Y, Miedema B, Hogg W, Wodchis WP, Aubrey-Bassler K. The influence of gender and other patient characteristics on health care-seeking behaviour: a QUALICOPC study. BMC Fam Pract 2016;17:38.
Tran VT, Porcher R, Pane I, Ravaud P. Course of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort. Nat Commun 2022;13(1):1812.
Walker AJ, MacKenna B, Inglesby P, Tomlinson L, Rentsch CT, Curtis HJ, et al. Clinical coding of long COVID in English primary care: a federated analysis of 58 million patient records in situ using OpenSAFELY. Br J Gen Pract 2021;71(712):e806-e14.
Wanga V, Chevinsky JR, Dimitrov LV, Gerdes ME, Whitfield GP, Bonacci RA, et al. Long-Term Symptoms Among Adults Tested for SARS-CoV-2 - United States, January 2020-April 2021. MMWR Morb Mortal Wkly Rep 2021;70(36):1235-41.
Westerlind E, Palstam A, Sunnerhagen KS, Persson HC. Patterns and predictors of sick leave after Covid-19 and long Covid in a national Swedish cohort. BMC Public Health 2021;21(1):1023.
World Health Organization. Emergency use ICD codes for COVID-19 disease outbreak; 2020a. Available from: https://www.who.int/standards/classifications/classification-of-diseases/emergency-use-icd-codes-for-covid-19-disease-outbreak [Accessed 28 June 2022.
World Health Organization. Updates 3 & 4 in relation to COVID-19 coding in ICD-10; 2020b. Available from: https://cdn.who.int/media/docs/default-source/classification/icd/covid-19/covid-19-coding-updates-3-4-combined.pdf?sfvrsn=39197c91_3 [Accessed 28 June 2022.