Symptoms and risk factors for long COVID in non-hospitalized adults

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Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02–8.39), hair loss (3.99, 3.63–4.39), sneezing (2.77, 1.40–5.50), ejaculation difficulty (2.63, 1.61–4.28) and reduced libido (2.36, 1.61–3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors.

Abstract

A retrospective analysis of primary care records in the United Kingdom reveals individual symptoms associated with SARS-CoV-2 infections, which persisted for 12 weeks or more after infection, as well as risk factors associated with developing long COVID.

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Most cited references 27

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6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

Chaolin Huang, Lixue Huang, Yeming Wang … (2021)

Background The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity. Methods We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7, 2020, and May 29, 2020. Patients who died before follow-up, patients for whom follow-up would be difficult because of psychotic disorders, dementia, or re-admission to hospital, those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism, those who declined to participate, those who could not be contacted, and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5–6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received severe acute respiratory syndrome coronavirus 2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences. Findings In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 (IQR 47·0–65·0) years and 897 (52%) were men. The follow-up study was done from June 16, to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 (175·0–199·0) days. Fatigue or muscle weakness (63%, 1038 of 1655) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1617) of patients. The proportions of median 6-min walking distance less than the lower limit of the normal range were 24% for those at severity scale 3, 22% for severity scale 4, and 29% for severity scale 5–6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5–6, and median CT scores were 3·0 (IQR 2·0–5·0) for severity scale 3, 4·0 (3·0–5·0) for scale 4, and 5·0 (4·0–6·0) for scale 5–6. After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80–3·25) for scale 4 versus scale 3 and 4·60 (1·85–11·48) for scale 5–6 versus scale 3 for diffusion impairment; OR 0·88 (0·66–1·17) for scale 4 versus scale 3 and OR 1·77 (1·05–2·97) for scale 5–6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58–0·96) for scale 4 versus scale 3 and 2·69 (1·46–4·96) for scale 5–6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up. Interpretation At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery. Funding National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Key Research and Development Program of China, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, and Peking Union Medical College Foundation.

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Post-acute COVID-19 syndrome

Ani Nalbandian, Kartik Sehgal, Aakriti Gupta … (2021)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.

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Deciding on the Number of Classes in Latent Class Analysis and Growth Mixture Modeling: A Monte Carlo Simulation Study

Karen L. Nylund, Tihomir Asparouhov, Bengt O. Muthén (2007)

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Author and article information

Contributors

Krishnarajah Nirantharakumar:

ORCID: http://orcid.org/0000-0002-6816-1279

K.Nirantharan@bham.ac.uk

Journal

Journal ID (nlm-ta): Nat Med

Journal ID (iso-abbrev): Nat Med

Title: Nature Medicine

Publisher: Nature Publishing Group US (New York )

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date (Electronic): 25 July 2022

Publication date PMC-release: 25 July 2022

Publication date (Print): 2022

Volume: 28

Issue: 8

Pages: 1706-1714

Affiliations

[1 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Institute of Applied Health Research, , University of Birmingham, ; Birmingham, UK

[2 ]Midlands Health Data Research UK, Birmingham, UK

[3 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, DEMAND Hub, , University of Birmingham, ; Birmingham, UK

[4 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Centre for Patient-Reported Outcomes Research, Institute of Applied Health Research, , University of Birmingham, ; Birmingham, UK

[5 ]National Institute for Health and Care Research (NIHR) Applied Research Collaboration (ARC) – West Midlands, Birmingham, UK

[6 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Birmingham Health Partners Centre for Regulatory Science and Innovation, , University of Birmingham, ; Birmingham, UK

[7 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, NIHR Birmingham-Oxford Blood and Transplant Research Unit (BTRU) in Precision Transplant and Cellular Therapeutics, , University of Birmingham, ; Birmingham, UK

[8 ]GRID grid.515306.4, ISNI 0000 0004 0490 076X, Clinical Practice Research Datalink, , Medicines and Healthcare products Regulatory Agency, ; London, UK

[9 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, School of Sport, Exercise and Rehabilitation Sciences, , University of Birmingham, ; Birmingham, UK

[10 ]GRID grid.83440.3b, ISNI 0000000121901201, Institute of Health Informatics, Faculty of Population Health Sciences, , University College London, ; London, UK

[11 ]GRID grid.7372.1, ISNI 0000 0000 8809 1613, Warwick Medical School, , University of Warwick, ; Coventry, UK

[12 ]GRID grid.5337.2, ISNI 0000 0004 1936 7603, School of Oral and Dental Sciences, , University of Bristol, ; Bristol, UK

[13 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, NIHR Surgical Reconstruction and Microbiology Research Centre, , University Hospital Birmingham and University of Birmingham, ; Birmingham, UK

[14 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Institute of Cancer and Genomic Sciences, , University of Birmingham, ; Birmingham, UK

[15 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, NIHR Birmingham Biomedical Research Centre, , University Hospital Birmingham and University of Birmingham, ; Birmingham, UK

[16 ]GRID grid.412563.7, ISNI 0000 0004 0376 6589, University Hospitals Birmingham NHS Foundation Trust, ; Birmingham, UK

[17 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Centre for Trauma Science Research, , University of Birmingham, ; Birmingham, UK

[18 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research, Institute of Inflammation and Ageing, , University of Birmingham, ; Birmingham, UK

[19 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, PIONEER HDR-UK Data Hub in acute care, , University of Birmingham, ; Birmingham, UK

[20 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, UK SPINE, , University of Birmingham, ; Birmingham, UK

[21 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Institute of Immunology and Immunotherapy, , University of Birmingham, ; Birmingham, UK

[22 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Institute for Mental Health, , University of Birmingham, ; Birmingham, UK

[23 ]GRID grid.450453.3, ISNI 0000 0000 9709 8550, Birmingham and Solihull Mental Health NHS Foundation Trust, ; Birmingham, UK

[24 ]Aparito Ltd, Wrexham, UK

[25 ]Patient and public involvement member, Birmingham, UK

Author information

Krishnarajah Nirantharakumar http://orcid.org/0000-0002-6816-1279

Sarah Hughes http://orcid.org/0000-0001-5656-1198

Joht Singh Chandan http://orcid.org/0000-0002-9561-5141

Kirsty Brown http://orcid.org/0000-0001-9403-1593

Nasir Bashir http://orcid.org/0000-0001-7416-7610

Georgios V. Gkoutos http://orcid.org/0000-0002-2061-091X

Olalekan Lee Aiyegbusi http://orcid.org/0000-0001-9122-8251

Alastair K. Denniston http://orcid.org/0000-0001-7849-0087

David C. Wraith http://orcid.org/0000-0003-2147-5614

Louise J. Jackson http://orcid.org/0000-0001-8492-0020

Melanie Calvert http://orcid.org/0000-0002-1856-837X

Shamil Haroon http://orcid.org/0000-0002-0096-1413

Article

Publisher ID: 1909

DOI: 10.1038/s41591-022-01909-w

PMC ID: 9388369

PubMed ID: 35879616

SO-VID: f0e3e719-a401-4467-80bd-c495b4235c3e

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 9 February 2022

Date accepted : 21 June 2022

Funding

Funded by: FundRef https://doi.org/10.13039/501100000272, DH | National Institute for Health Research (NIHR);

Award ID: COV-LT-0013

Award ID: NIHR132914

Award ID: 300688

Award Recipient : Krishnarajah Nirantharakumar Joht Singh Chandan Farah Kidy

Funded by: National Institute for Health and Care Research Applied Research Council, West Midlands NIHR Birmingham-Oxford Blood and Transplant Research Institute in Precision Transplant and Cellular Therapeutics at the University of Birmingham and University Hospitals Birmingham NHS Foundation

Funded by: FundRef https://doi.org/10.13039/100012141, University Hospitals Bristol NHS Foundation Trust;

Award ID: NIHR203304

Award Recipient : Joht Singh Chandan

Funded by: FundRef https://doi.org/10.13039/501100000274, British Heart Foundation (BHF);

Funded by: THIS institute NIHR University College London Biomedical Research Council

Funded by: NIHR Birmingham ECMC NIHR Birmingham SRMRC Nanocommons H2020-EU (731032) MAESTRIA (Grant agreement ID 965286) MRC Heath Data Research UK (HDRUK/CFC/01)

Funded by: FundRef https://doi.org/10.13039/100005564, Gilead Sciences (Gilead);

Funded by: FundRef https://doi.org/10.13039/100008897, Janssen Pharmaceuticals (Janssen Pharmaceuticals, Inc.);

Funded by: FundRef https://doi.org/10.13039/100009756, Sarcoma UK;

Funded by: NIHR Birmingham Biomedical Research Council NIHR Applied Research Council, West Midlands NIHR Birmingham-Oxford Blood and Transplant Research Institute in Precision Transplant and Cellular Therapeutics at the University of Birmingham and University Hospitals Birmingham NHS Foundation

Funded by: FundRef https://doi.org/10.13039/501100006041, Innovate UK;

Funded by: NIHR SRMRC NIHR Birmingham-Oxford Blood and Transplant Research Institute in Precision Transplant and Cellular Therapeutics at the University of Birmingham and University Hospitals Birmingham NHS Foundation

Funded by: FundRef https://doi.org/10.13039/100004440, Wellcome Trust (Wellcome);

Funded by: FundRef https://doi.org/10.13039/501100000265, RCUK | Medical Research Council (MRC);

Funded by: FundRef https://doi.org/10.13039/501100000266, RCUK | Engineering and Physical Sciences Research Council (EPSRC);

Funded by: FundRef https://doi.org/10.13039/501100000351, British Lung Foundation (BLF);

Funded by: FundRef https://doi.org/10.13039/501100001923, DH | NIHR | Health Services Research Programme (NIHR Health Services Research Programme);

Funded by: NIHR EME NIHR HTA HDR-UK Alpha 1 Foundation

Funded by: FundRef https://doi.org/10.13039/100011696, Scar Free Foundation;

Funded by: Versus Arthritis FOREUM UKSPINE

Funded by: National Institute for Health Research Applied Health Research, West Midlands

Funded by: National Institute for Health Research Birmingham Biomedical Research Council

Funded by: FundRef https://doi.org/10.13039/100011715, Macmillan Cancer Support (Macmillan);

Funded by: FundRef https://doi.org/10.13039/501100002066, GlaxoSmithKline foundation (GSK);

Funded by: FundRef https://doi.org/10.13039/100008799, Gilead Foundation;

Funded by: NIHR Birmingham Biomedical Research Centre NIHR Surgical Reconstruction and Microbiology Research Centre NIHR Birmingham-Oxford Blood and Transplant Research Unit (BTRU) in Precision Transplant and Cellular Therapeutics NIHR Applied Research Collaboration (ARC), West Midlands at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust Health Data Research UK SPINE UK UKRI UCB Pharma