Long COVID: mechanisms, risk factors and recovery

doi:10.1113/EP090802

Review

. 2023 Jan;108(1):12-27.

doi: 10.1113/EP090802. Epub 2022 Nov 22.

Long COVID: mechanisms, risk factors and recovery

Rónan Astin^{1

2}, Amitava Banerjee^{3

4}, Mark R Baker⁵, Melanie Dani⁶, Elizabeth Ford⁷, James H Hull^{8

9}, Phang Boon Lim⁶, Melitta McNarry¹⁰, Karl Morten^{10

11}, Oliver O'Sullivan^{12

13}, Etheresia Pretorius^{14

15}, Betty Raman^{16

17}, Demetris S Soteropoulos⁵, Maxime Taquet^{18

19}, Catherine N Hall²⁰

Affiliations

¹ Department of Respiratory Medicine, University College London Hospitals NHS Foundation Trust, London, UK.
² Centre for Human Health and Performance, Institute for Sport Exercise and Health, University College London, London, UK.
³ Institute of Health Informatics, University College London, London, UK.
⁴ Department of Cardiology, Barts Health NHS Trust, London, UK.
⁵ Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
⁶ Imperial Syncope Unit, Imperial College Healthcare NHS Trust, London, UK.
⁷ Brighton and Sussex Medical School, Falmer, UK.
⁸ Institute of Sport, Exercise and Health (ISEH), Division of Surgery and Interventional Science, University College London, London, UK.
⁹ Royal Brompton Hospital, London, UK.
¹⁰ Applied Sports, Technology, Exercise and Medicine Research Centre, Swansea University, Swansea, UK.
¹¹ Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.
¹² Academic Department of Military Rehabilitation, Defence Medical Rehabilitation Centre Stanford Hall, Loughborough, UK.
¹³ School of Medicine, University of Nottingham, Nottingham, UK.
¹⁴ Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa.
¹⁵ Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.
¹⁶ Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, Oxford, UK.
¹⁷ Radcliffe Department of Medicine, Division of Cardiovascular Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹⁸ Department of Psychiatry, University of Oxford, Oxford, UK.
¹⁹ Oxford Health NHS Foundation Trust, Oxford, UK.
²⁰ School of Psychology and Sussex Neuroscience, University of Sussex, Falmer, UK.

PMID: 36412084
PMCID: PMC10103775
DOI: 10.1113/EP090802

Review

Long COVID: mechanisms, risk factors and recovery

Rónan Astin et al. Exp Physiol. 2023 Jan.

. 2023 Jan;108(1):12-27.

doi: 10.1113/EP090802. Epub 2022 Nov 22.

Authors

Affiliations

¹ Department of Respiratory Medicine, University College London Hospitals NHS Foundation Trust, London, UK.
² Centre for Human Health and Performance, Institute for Sport Exercise and Health, University College London, London, UK.
³ Institute of Health Informatics, University College London, London, UK.
⁴ Department of Cardiology, Barts Health NHS Trust, London, UK.
⁵ Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
⁶ Imperial Syncope Unit, Imperial College Healthcare NHS Trust, London, UK.
⁷ Brighton and Sussex Medical School, Falmer, UK.
⁸ Institute of Sport, Exercise and Health (ISEH), Division of Surgery and Interventional Science, University College London, London, UK.
⁹ Royal Brompton Hospital, London, UK.
¹⁰ Applied Sports, Technology, Exercise and Medicine Research Centre, Swansea University, Swansea, UK.
¹¹ Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.
¹² Academic Department of Military Rehabilitation, Defence Medical Rehabilitation Centre Stanford Hall, Loughborough, UK.
¹³ School of Medicine, University of Nottingham, Nottingham, UK.
¹⁴ Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa.
¹⁵ Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.
¹⁶ Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, Oxford, UK.
¹⁷ Radcliffe Department of Medicine, Division of Cardiovascular Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹⁸ Department of Psychiatry, University of Oxford, Oxford, UK.
¹⁹ Oxford Health NHS Foundation Trust, Oxford, UK.
²⁰ School of Psychology and Sussex Neuroscience, University of Sussex, Falmer, UK.

PMID: 36412084
PMCID: PMC10103775
DOI: 10.1113/EP090802

Abstract

New findings: What is the topic of this review? The emerging condition of long COVID, its epidemiology, pathophysiological impacts on patients of different backgrounds, physiological mechanisms emerging as explanations of the condition, and treatment strategies being trialled. The review leads from a Physiological Society online conference on this topic. What advances does it highlight? Progress in understanding the pathophysiology and cellular mechanisms underlying Long COVID and potential therapeutic and management strategies.

Abstract: Long COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS-CoV-2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery. This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post-viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post-viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance - namely the military and elite athletes. The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID-related changes in physiology - including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve. We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro-clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations. Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition.

Keywords: ME/CFS; SARS-CoV-2; cardiovascular; coagulation; dysautonomia; fatigue; long COVID; respiratory.

PubMed Disclaimer

Conflict of interest statement

A.B. is a Trustee of the South Asian Health Foundation and of Long COVID SOS. B.R. has received speaker honorarium fees from Axcella Therapeutics.

Figures

**FIGURE 1**
Clotting pathologies in long COVID. ROS, reactive oxygen species. Created with BioRender.com.

See this image and copyright information in PMC

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References

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1. Ajaz, S. , McPhail, M. J. , Singh, K. K. , Mujib, S. , Trovato, F. M. , Napoli, S. , & Agarwal, K. (2021). Mitochondrial metabolic manipulation by SARS‐CoV‐2 in peripheral blood mononuclear cells of patients with COVID‐19. American Journal of Physiology. Cell Physiology, 320(1), C57–C65. - PMC - PubMed
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1. Althaus, K. , Marini, I. , Zlamal, J. , Pelzl, L. , Singh, A. , Häberle, H. , Mehrländer, M. , Hammer, S. , Schulze, H. , Bitzer, M. , Malek, N. , Rath, D. , Bösmüller, H. , Nieswandt, B. , Gawaz, M. , Bakchoul, T. , & Rosenberger, P. (2021). Antibody‐induced procoagulant platelets in severe COVID‐19 infection. Blood, 137(8), 1061–1071. - PMC - PubMed
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[1] Abrams, R. M. C. , Simpson, D. M. , Navis, A. , Jette, N. , Zhou, L. , & Shin, S. C. (2022). Small fiber neuropathy associated with SARS‐CoV‐2 infection. Muscle & Nerve, 65, 440–443. - PMC - PubMed

[2] Abrams, R. M. C. , Simpson, D. M. , Navis, A. , Jette, N. , Zhou, L. , & Shin, S. C. (2022). Small fiber neuropathy associated with SARS‐CoV‐2 infection. Muscle & Nerve, 65, 440–443. - PMC - PubMed

[3] Ajaz, S. , McPhail, M. J. , Singh, K. K. , Mujib, S. , Trovato, F. M. , Napoli, S. , & Agarwal, K. (2021). Mitochondrial metabolic manipulation by SARS‐CoV‐2 in peripheral blood mononuclear cells of patients with COVID‐19. American Journal of Physiology. Cell Physiology, 320(1), C57–C65. - PMC - PubMed

[4] Ajaz, S. , McPhail, M. J. , Singh, K. K. , Mujib, S. , Trovato, F. M. , Napoli, S. , & Agarwal, K. (2021). Mitochondrial metabolic manipulation by SARS‐CoV‐2 in peripheral blood mononuclear cells of patients with COVID‐19. American Journal of Physiology. Cell Physiology, 320(1), C57–C65. - PMC - PubMed

[5] Al‐Aly, Z. , Bowe, B. , & Xie, Y. (2022). Long COVID after breakthrough SARS‐CoV‐2 infection. Nature Medicine, 28(7), 1461–1467. - PMC - PubMed

[6] Al‐Aly, Z. , Bowe, B. , & Xie, Y. (2022). Long COVID after breakthrough SARS‐CoV‐2 infection. Nature Medicine, 28(7), 1461–1467. - PMC - PubMed

[7] Althaus, K. , Marini, I. , Zlamal, J. , Pelzl, L. , Singh, A. , Häberle, H. , Mehrländer, M. , Hammer, S. , Schulze, H. , Bitzer, M. , Malek, N. , Rath, D. , Bösmüller, H. , Nieswandt, B. , Gawaz, M. , Bakchoul, T. , & Rosenberger, P. (2021). Antibody‐induced procoagulant platelets in severe COVID‐19 infection. Blood, 137(8), 1061–1071. - PMC - PubMed

[8] Althaus, K. , Marini, I. , Zlamal, J. , Pelzl, L. , Singh, A. , Häberle, H. , Mehrländer, M. , Hammer, S. , Schulze, H. , Bitzer, M. , Malek, N. , Rath, D. , Bösmüller, H. , Nieswandt, B. , Gawaz, M. , Bakchoul, T. , & Rosenberger, P. (2021). Antibody‐induced procoagulant platelets in severe COVID‐19 infection. Blood, 137(8), 1061–1071. - PMC - PubMed

[9] Aranow, C. , Atish‐Fregoso, Y. , Lesser, M. , Mackay, M. , Anderson, E. , Chavan, S. , Zanos, T. P. , Datta‐Chaudhuri, T. , Bouton, C. , Tracey, K. J. , & Diamond, B. (2021). Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: A randomised, double‐blind, sham‐controlled pilot trial. Annals of the Rheumatic Diseases, 80(2), 203–208. - PubMed

[10] Aranow, C. , Atish‐Fregoso, Y. , Lesser, M. , Mackay, M. , Anderson, E. , Chavan, S. , Zanos, T. P. , Datta‐Chaudhuri, T. , Bouton, C. , Tracey, K. J. , & Diamond, B. (2021). Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: A randomised, double‐blind, sham‐controlled pilot trial. Annals of the Rheumatic Diseases, 80(2), 203–208. - PubMed

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Long COVID: mechanisms, risk factors and recovery

Affiliations

Long COVID: mechanisms, risk factors and recovery

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Abstract

Conflict of interest statement

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Abstract

Conflict of interest statement

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