As of the 8 June 2021, there have been over 170 million cases of covid-19 and 3.7 million deaths worldwide. In the UK, over 4.5 million cases have been reported with a total of approximately 127,500 deaths. [1,2] However, it is well recognised that case numbers and deaths from covid-19 globally are probably under reported.
Beyond the acute symptoms of covid-19, there is the spectre of long covid for many. Estimates suggest that long covid symptoms are found in 13% of patients at 28 days and in 22% 5-12 weeks from the onset of acute infection [3-6]. We simply do not yet know the full scale of the problem.
Long covid may be the result of several possible pathological mechanisms that have not yet been conclusively determined [3,7,8]. A spectrum of risk factors is likely, such as severe acute infection and a lengthy in-patient stay. Demographic factors may play a part—older women and people with a high body mass index seem particularly affected. Neurological and neuropsychiatric symptoms in long covid such as autonomic dysfunction and fatigue are likely to be some of the most challenging problems to understand and treat. Autonomic dysfunction may be found to be a risk factor for symptom persistence, as well as a possible mechanism involved in long covid.  To understand the clinical implications of long covid fully, however, more information is required.
So far little evidence is available to guide the management of long covid in clinical practice. Physical and psychological rehabilitation is needed, but only generalised treatment is possible until we understand the patterns and factors causing persistent symptoms. Recommendations from the National Institute for Health and Care Excellence (NICE) for routine blood, cardiac, and respiratory function tests do not include assessment of neuropsychiatric, neurological, and pain symptoms even though these predominate in surveys of patients with long covid.  We argue that in-depth assessment from these specialities will provide a more holistic approach to managing patients with long covid. To achieve this, it is necessary for clinical services to be re-aligned to cover shortfalls in funding, staff, and clinical leadership to deliver longterm care to these patients. The economic fallout from the pandemic means that such resources may be scarce for the foreseeable future, but generic treatments based on “traditional” rehabilitation models may waste valuable time and money unless specific patient vulnerabilities are first identified. To achieve this, evidence should be synthesised in a “living” format such as a living systematic review (LSR). LSR is defined by the Cochrane community as a systematic review that is continually updated, incorporating relevant new evidence as it becomes available, allowing better use of data from existing electronic health records to enable evidence-based practice.
To date, it is unknown whether covid-19 variants affect the risk of long covid. Different variants seem to affect virulence and acute symptoms, such as anosmia, but it remains unknown whether new variants could trigger unexpected post-infectious symptoms, emulating the possible link between the 1918 influenza pandemic, Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), and encephalitis lethargica.  Furthermore, it remains to be seen whether vaccination in those previously infected affects the risk of long covid.
The fear of influenza-covid co-infection did not materialise until late in 2020. Strict covid-19 restrictions are now being eased in many parts of the world, including the UK. Only time will tell whether this will increase the risk of joint or sequential infections in the future. Covid and influenza vaccinations may reduce the risk of the overall burden of severe acute infection but may not affect prolonged post-infectious symptoms.
Collecting epidemiological data, identifying symptom clusters, and evaluating representative patients on the basis of these could provide insights into long covid. Life-course epidemiological methods may be useful when constructing studies to explore long covid. Intensive clinical research that could be set up rapidly alongside evidence synthesis may lead to a better understanding of the pathophysiology of long covid. Furthermore, such research may benefit patients with pre-existing neurological disorders, such as Parkinson’s disease, multiple sclerosis, and chronic fatigue syndrome. 
Considerable health resources have been expended on tackling acute covid infections. The successful vaccination roll-out in the UK and internationally promises to reduce acute infection, disease severity, and transmission. The same investment is needed to better understand long covid, and for clinical services to develop long term treatments.
MS Chong, The National Hospital for Neurology and Neurosurgery London Queen Square and Cleveland Street
Ashish Shetty, The National Hospital for Neurology and Neurosurgery London Queen Square and Cleveland Street and University College London NHS Foundation Trust
Shane Delamont, Kings College Hospital London
Mayur Bodani, Kent and Medway NHS and Social Care Partnership Trust and School of Psychology, University of Kent, Canterbury
Peter Phiri, Research & Development Department, Southern Health NHS Foundation Trust and Primary Care, Population Sciences and Medical Education, Faculty of Medicine, University of Southampton
Gayathri Delanerolle, University of Oxford, Oxford
Acknowledgements: This paper is part of the multifaceted EPIC project that is sponsored by Southern Health NHS Foundation Trust and in collaboration with the University of Oxford.
Competing interests: PP has received research grant from Novo Nordisk, and other, educational from Queen Mary University of London, other from John Wiley & Sons, other from Otsuka, outside the submitted work. GD has received funding from the NIHR. All other authors report no conflict of interests for this article.
The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, the Department of Health and Social Care or the academic institutions.
- WHO Coronavirus Disease (COVID-19) Dashboard. Retrieved from https://covid19.who.int/
- Davis HE, Assaf GS, Lisa McCorkell L et al, Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact. https://doi.org/10.1101/2020.12.24.20248802
- NIHR. Living with covid-19. A dynamic review of the evidence around ongoing covid-19 symptoms (often called long covid). October 2020. https://evidence.nihr.ac.uk/themedreview/living-with-covid19.
- COVID-19 rapid guideline: managing the long-term effects of COVID-19 NICE guideline [NG188] https://www.nice.org.uk/guidance/ng188
- Sudre CH, Murray B, Varsavsky T et. al., Attributes and predictors of Long-COVID: analysis of COVID cases and their symptoms collected by the Covid Symptoms Study App https://doi.org/10.1101/2020.10.19.20214494
- The prevalence of long COVID symptoms and COVID-19 complications https://www.ons.gov.uk/news/statementsandletters/theprevalenceoflongcovidsymptomsandcovid19complications
- Dennis A, Malgorzata W, Kapur S, et. al., Multi-organ impairment in low-risk individuals with long COVID
- Goldstein DS. The extended autonomic system, dyshomeostasis, and COVID‑19. Clinical Autonomic Research https://doi.org/10.1007/s10286-020-00714-0
- Dani M, Dirksen AA, Taraborrelli P et. al., Autonomic dysfunction in ‘long COVID’: rationale, physiology and management strategies. Clinical Medicine 2021 Vol 21, No 1: e63–7
- Giordiano A, Schwarz G, Cacciaguerra L, Esposito F, Massimo F. COVID-19: can we learn from encephalitis lethargica? Lancet Neurol. 2020 Jul; 19(7): 570
- Penner I-K and Friedemann P. Fatigue as a symptom or comorbidity of neurological diseases. Nat Rev Neurol. 2017 Nov;13(11):662-675