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. 2022 Aug;28(8):1706-1714.
doi: 10.1038/s41591-022-01909-w. Epub 2022 Jul 25.

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

Anuradhaa Subramanian  1 , Krishnarajah Nirantharakumar  2   3   4 , Sarah Hughes  1   5   6   7   8 , Puja Myles  9 , Tim Williams  9 , Krishna M Gokhale  1 , Tom Taverner  1 , Joht Singh Chandan  1 , Kirsty Brown  1   10 , Nikita Simms-Williams  1 , Anoop D Shah  11 , Megha Singh  1 , Farah Kidy  1   12 , Kelvin Okoth  1 , Richard Hotham  1 , Nasir Bashir  13 , Neil Cockburn  1 , Siang Ing Lee  1 , Grace M Turner  1   5   14 , Georgios V Gkoutos  15   16   17   18   19 , Olalekan Lee Aiyegbusi  1   5   6   7   8   18 , Christel McMullan  1   5   8   14   20 , Alastair K Denniston  15   16   5   7   18   19 , Elizabeth Sapey  19   21   22 , Janet M Lord  14   18   21   23 , David C Wraith  18   24 , Edward Leggett  9 , Clare Iles  9 , Tom Marshall  1 , Malcolm J Price  1   18 , Steven Marwaha  25   26 , Elin Haf Davies  27 , Louise J Jackson  1 , Karen L Matthews  28 , Jenny Camaradou  28 , Melanie Calvert  1   15   16   5   6   7   8   14   18   22 , Shamil Haroon  1
Affiliations

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

Anuradhaa Subramanian et al. Nat Med. 2022 Aug.

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.

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Conflict of interest statement

M.C. is Director of the Birmingham Health Partners Center for Regulatory Science and Innovation and Director of the Center for Patient-Reported Outcomes Research and is an NIHR Senior Investigator. M.C. receives funding from the NIHR Birmingham Biomedical Research Center (BRC), NIHR Surgical Reconstruction and Microbiology Research Center (SRMRC), NIHR Birmingham-Oxford Blood and Transplant Research Unit (BTRU) in Precision Transplant and Cellular Therapeutics and NIHR Applied Research Collaboration (ARC) West Midlands at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Health Data Research UK, Innovate UK (part of UK Research and Innovation), Macmillan Cancer Support, SPINE UK, UKRI, UCB Pharma, Janssen, GSK and Gilead. M.C. has received personal fees from Astellas, Aparito, CIS Oncology, Takeda, Merck, Daiichi Sankyo, Glaukos, GSK and the Patient-Centered Outcomes Research Institute outside the submitted work. S.E.H. receives funding from NIHR ARC, West Midlands and the NIHR BTRU in Precision Transplant and Cellular Therapeutics at the University of Birmingham. S.E.H. declares personal fees from Cochlear and Aparito outside the submitted work. O.L.A. receives funding from the NIHR Birmingham BRC, NIHR ARC, West Midlands, NIHR BTRU in Precision Transplant and Cellular Therapeutics at the University of Birmingham and University Hospitals Birmingham NHS Foundation, Innovate UK, Gilead Sciences, Janssen Pharmaceuticals and Sarcoma UK. O.L.A. declares personal fees from Gilead Sciences, GSK and Merck outside the submitted work. C.M. receives funding from NIHR SRMRC, NIHR BTRU in Precision Transplant and Cellular Therapeutics and Innovate UK and has received personal fees from Aparito outside the submitted work. A.D.S. is supported by a postdoctoral fellowship from THIS Institute, NIHR University College London Hospitals BRC, grants from NIHR and British Heart Foundation Accelerator Award. E.S. has received grants from the Wellcome Trust, MRC, NIHR EME, NIHR HTA, HDR-UK, BLF, EPSRC and Alpha 1 Foundation in the last 36 months. She has been an honorarium for lectures about COVID-19 treatments, which are run by GSK, attended a virtual conference at the European Respiratory Society in 2020 that was funded by AstraZeneca and participated in an advisory board for COPD, which is run by Boehringer Ingelheim. S.M. has received funding from NIHR (RfPB, PGfAR, HTA and EME streams), UKRI, ESRC and the Midlands Engine. He has attended educational events funded by Psychiatric Genetic Testing, Janssen and Lundbeck in the last 5 years. P.M., T.W., C.I. and E.L. are employees of CPRD, the data custodians for CPRD Aurum. CPRD is jointly sponsored by the UK Government’s MHRA and NIHR. As a not-for-profit UK Government body, CPRD seeks to recoup the cost of delivering its research services to academic, industry and government researchers through research user license fees. J.C. receives funding from NIHR on PPI from a study at UCL (NIHR132914) and a study at University Hospitals Bristol (NIHR203304). J.C. is a lay member on the NICE COVID expert panel and a citizen partner on the COVID END Evidence Synthesis Global Horizon Scanning panel. J.C. declares personal fees from MEDABLE, GlaxoSmithKline and Roche Canada outside of submitted work. K.L.M. is a trustee and volunteer at long COVID SOS. K.L.M. is on the long COVID Advisory Board for Dysautonomia International and is employed by NIHR. T.M. receives funding from NIHR ARC, West Midlands. G.V.G. receives funding from the NIHR Birmingham ECMC, NIHR Birmingham SRMRC, Nanocommons H2020-EU (731032), MAESTRIA (grant agreement no. 965286) and the MRC Health Data Research UK (HDRUK/CFC/01). J.M.L. receives funding from the MRC, Versus Arthritis, NIHR, FOREUM, UKSPINE and the Scar Free Foundation and declares personal fees from Bayer. F.K. is supported by an NIHR Doctoral Fellowship award (grant no. 300688). M.J.P. is supported by NIHR BRC. All other co-authors declare no competing interests. The views expressed are those of the investigators, and the funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Figures

Fig. 1
Fig. 1
Symptoms associated with SARS-CoV-2 ≥ 12 weeks after infection.
Extended Data Fig. 1
Extended Data Fig. 1
Kernel density plot of propensity scores of patients infected with SARS CoV-2 and comparator cohort of patients with no recorded evidence of SARS CoV-2 infection, before and after propensity score matching.
Extended Data Fig. 2
Extended Data Fig. 2
Symptoms associated with SARS CoV-2 ≥ 12 weeks post-infection before and after 31 August 2020 (first and second surges of the pandemic in the UK) – Part A.
Extended Data Fig. 3
Extended Data Fig. 3
Symptoms associated with SARS CoV-2 ≥ 12 weeks post-infection before and after 31 August 2020 (first and second surges of the pandemic in the UK) – Part B.
Extended Data Fig. 4
Extended Data Fig. 4
Symptoms associated with SARS CoV-2 ≥ 12 weeks post-infection before and after 31 August 2020 (first and second surges of the pandemic in the UK) – Part C.
Extended Data Fig. 5
Extended Data Fig. 5
Elbow plot to determine the optimal number of classes.
Extended Data Fig. 6
Extended Data Fig. 6
Symptom clusters among patients with long COVID from latent class analysis.
See this image and copyright information in PMC

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