Long COVID

Original Editor - Darren Brown Top Contributors -  

Introduction[edit | edit source]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease (COVID-19) [1]. The effects of COVID-19 have been characterised across different time points:

  • Acute COVID-19 infection with signs and symptoms of COVID-19 for up to 4 weeks.
  • Ongoing symptomatic COVID-19 with signs and symptoms of COVID-19 from 4 weeks up to 12 weeks.
  • Long term consequences of COVID-19 which usually presents with clusters of symptoms, often overlapping, which can fluctuate and change over time and can affect any system in the body for more than 12 weeks.[2]

The long term sequelae of COVID-19 awaits consensus definition, and a variety of nomenclature has been used to describe the long term signs and symptoms of COVID-19. This includes the patient directed terms "Long Covid" [3][4][5][6][7][8][9], "Long-Haul Covid" [4][10] and "Long Haulers" [11][12], plus other terms including "Post COVID-19 Condition" [13], "Post-COVID-19 syndrome" [2][14], "Post-COVID Syndrome" [15], "Post-Acute COVID-19" [16], and "Post-Acute COVID-19 syndrome"[15]. The policy brief (no. 39) from the World Health Organization regional office for Europe, used the term "Long COVID" [17]. For the purposes of consistency, this page will refer to the long term consequences of COVID-19 as "Long COVID" and to "People living with Long COVID". We will refer to "Long COVID" because this term acknowledges that disease cause and course are as yet unknown, makes clear that “mild” COVID-19 is not necessarily mild, avoids “chronic,” “post” and “syndrome” that may delegitimise people's experiences, draws attention to morbidity, and centres people with disability [3]. We will refer to "People living with Long COVID" to align with existing person first language,[18] applying knowledge from other health care conditions that are often associated with stigma.[19]

What is Long COVID?[edit | edit source]

Long Covid has been preliminarily defined by The National Institute for Health and Care Excellence (NICE), the Scottish Intercollegiate Guidelines Network, and the Royal College of General Practitioners, as the presence of signs and symptoms that develop during or following an infection consistent with COVID-19 which continue for 12-weeks or more and are not explained by an alternative diagnosis. This includes both ongoing symptomatic COVID-19 (from 4 to 12 weeks) and "Post-COVID Syndrome" (12-weeks or more).[20]

The rapid and dynamic review of Long Covid evidence by the National Institute for Health Research (NIHR) suggests that Long Covid may be made up of 4 phenotypes [18]:

  • post-intensive care
  • post-viral fatigue
  • permanent organ damage
  • long-term COVID

Long COVID affects people who have been hospitalised with acute COVID-19 and those who managed in a community setting. There is growing evidence to suggest that individuals who have suffered from both mild or severe COVID-19 can experience prolonged symptoms or develop Long COVID.[21][22][23][24][25][26][27][28][29] Consensus has not yet been reached on an internationally agreed Long COVID case definition[6][17][30][31], however there is mounting evidence that Long COVID is both common and debilitating.[17] Attempts have been made to characterise Long Covid as prolonged with multi-system involvement and significant disability.[30][32]

Long COVID Symptoms[edit | edit source]

Long COVID usually presents as clusters of symptoms, often overlapping, which can fluctuate and change over time and can affect any system in the body. [17][20][30][33][34][35][36] Long COVID can include a range of different signs and symptoms across body systems including, but not limited to: pulmonary, cardiovascular, gastrointestinal, reproductive, genitourinary, endocrine, renal, dermatologic, musculoskeletal, neurological, neuropsychiatric, immunological, ophthalmic, and audiological.[30] A list of common Long COVID symptoms is provided by The National Institute for Health and Care Excellence (NICE) [20].

The most common Long Covid symptom is fatigue.[30][33][37][38][29][39][40][41][25][42][43][44][45][46][47][27][48][49] The most frequently reported Long COVID symptoms after 6 months include fatigue, post-exertion malaise, and cognitive dysfunction [30]. The multidimensional, episodic and often unpredictable nature of Long COVID has been described as "relapsing and remitting"[34], whereby 86% of people with Long COVID report relapses over 7 months, with physical activity, stress, exercise and mental activity being the most common triggers of relapses.[30] The trajectory of Long COVID is heterogenous with some improving over time, some worsening and others stable, with many experiencing ongoing fluctuating symptoms after 6 months[30]. Among a sample of 47,780 people hospitalised with COVID-19 in the UK, 29.4% are readmitted within a few months, with increased risk of hospital readmission and organ impairment compared to matched controls.[50] Among a sample of 2,649 adults hospitalised with confirmed COVID-19 in Russia, 6-8 months after discharge from the hospital, around a half (47.1%) of patients reported at least one long-standing symptom since discharge, with fatigue (21.2%), shortness of breath (14.5%) and forgetfulness (9.1%) the most common long-standing symptoms reported.[47] Among a sample of 325 admitted to hospitals across the UK with confirmed COVID-19, half of participants reported feeling not fully recovered from COVID-19 (median follow-up 7 months), three quarters experienced fatigue, half were more breathless compared to before and around a quarter had a new disability in sight, walking, memory, self-care and/or communication.[51] Furthermore, outcomes were worse in working age females than males, with females under 50 being over five times more likely to report incomplete recovery, over five times more likely to report a new disability, more likely to have severe fatigue, and more than six times more likely to report increased breathless than males under 50.[51] It is estimated that 30% of people not hospitalised with "mild" acute symptoms, continue to have symptoms 9 months after infection.[27] Preliminary evidence suggests children also experience Long COVID symptoms similar to adults.[52]

Long COVID Prevalence[edit | edit source]

Estimating the prevalence of Long COVID symptoms poses several challenges due to current lack of consensus definition and limited data collection in national surveys. The COVID-19 Infection Survey[53] is a nationally representative sample of the UK community population, from which it is has been estimated that around 1 in 5 people exhibit Long COVID symptoms for 5 weeks or longer, and around 1 in 10 exhibit Long COVID symptoms for 12 weeks or longer [7][54]. The Zurich Coronavirus Cohort Study[48] recruited 437 SARS-CoV-2 positive individuals. Symptoms at diagnosis were reported by 90% of participants, of which 16%, 40%, 30% & 13% reported mild, moderate, severe and very severe symptoms respectively. Within two weeks of infection, 20% were hospitalised. At 6 months, 26% reported not having returned to normal health state; 31% among males and 21% among females. Furthermore, 23% among the non-hospitalised and 39% among the hospitalised reported not having fully recovered. The World Health Organization regional office for Europe Policy Brief on Long COVID, provides a selected evidence summary on Long COVID prevalence among both people non-hospitalised and hospitalsed.[17]

Pathological Process[edit | edit source]

The aetiology and pathophysiological causes of Long COVID symptoms remains unknown. Initial hypothesis include: viral persistence [55][56][57][58], continued hyperactive immune response[59][60][61], cellular metabolic dysfunction[62], auto-antibodies[63][64], neurological dysfunction[65][66][67][68], neuroimmunology[69], neurological inflammation[70], and organ impairment[29] including cardiac impairment [29][71][72][73][74][75]. Musculoskeletal short- and long-term consequences of COVID-19 are also discussed.[76] More research is required to understand the mechanisms by which Long COVID develops.[17]

Long COVID Management[edit | edit source]

The National Institute for Health and Care Excellence (NICE) published a rapid guideline on managing Long COVID[20], which covers identifying, assessing and managing Long COVID across all health care settings for adults, children and young people who have ongoing symptoms 4 weeks or more after the start of acute COVID-19. The novel nature of Long COVID has resulted in urgent calls for more research to fill existing gaps in knowledge [77]. Co-designed quality standards for Long COVID services are proposed with potential patient care pathway model, highlighting equity and ease of access, minimal patient care burden, clinical responsibility, a multidisciplinary and evidence-based approach, and patient involvement.[78] A multi-disciplinary approach assessment and management of Long COVID is essential.[17] Encompassing a disability model could improve clinicians’ responses to Long COVID.[79]

.

Outcome Measures[edit | edit source]

The National Institute for Health Research (NIHR) has encouraged the use of the International Classification of Functioning Disability and Health (ICF) to provide a framework and standard language for the description of health and health-related state, due to current insufficient evidence to provide guidance.[18] The ICF has been operationalised into the ICF Browser, ICF Checklist, and World Health Organization Disability Assessment Schedule (WHODAS) 2.0.

Some studies have performed a level of functional assessment, including:

It may be suitable to assess for post-exertion malaise[95] using measurement tools such as the DePaul Symptom Questionnaire[96]. People living with Long COVID report post-exertion malaise,[30] and the presence of this symptom would suggest exercise is not a safe rehabilitation intervention.[97]

The World Health Organization (WHO) invites clinicians and patients to collect information on COVID-19 in a systematic way and contribute clinical data to the WHO Clinical Platform to expand knowledge on Long COVID (here termed by WHO "Post-COVID-19 condition"), and support patient care and public health interventions. WHO’s Post COVID case report form (CRF) has been designed to report standardised clinical data from individuals after hospital discharge or after the acute illness to examine the medium- and long-term consequences of COVID-19. The forms will be available in multiple languages. The CRF includes questions on functioning and disability (section 2.5) adopted from WHODAS 2.0 12-item self-report questionnaire.

Management / Interventions[edit | edit source]

There is currently insufficient evidence on safe and effective interventions for management of Long COVID symptoms and impairments or disability. The World Health Organization has called on countries to offer people living with Long COVID more rehabilitation.[98]

The National Institute for Health and Care Excellence (NICE) has cautioned against the use of graded exercise therapy (GET) for managing post-viral fatigue[77], in response to draft guidance updates on the management of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS).[97][99] Substantial concerns exist regarding the potential for harm in respect to GET as an intervention for ME/CFS.[100] Post-exertion malaise is a symptom experienced by people living with ME/CFS, [101] and is characterised as the worsening of symptoms by exertion including physical, cognitive and emotional activities,[102][103][104] which would prohibit exercise interventions. Among a sample of 3,762 people living with Long COVID, post-exertion malaise was reported by 72.2%, plus exercise is a common trigger for symptom relapses[30][32] warranting caution with exercise as a rehabilitation intervention for Long COVID and people living with COVID-19.

Groups representing people living with Long COVID have advocated for a risk stratification approach to exercise as a rehabilitation intervention. A focus is needed on assessing and excluding post-exertion malaise[95][96], plus screening for potential cardiac involvement[105] due to 32% prevalence of cardiac impairment among a young and low-risk population of people living with Long COVID and persistent symptoms.[29]

The National Health Service (NHS) provides free online self-management rehabilitation for people recovering from COVID-19 called "Your COVID Recovery".

Mount Sinai Long COVID Recovery programme provides free online breath-work for Long COVID called "STASIS".

The National Institute for Health Research (NIHR) recently funded a research award for the Rehabilitation Exercise and psycholoGical support After covid-19 InfectioN (REGAIN) study.[106]

Activity management or pacing is likely to be a safe and effective intervention for managing fatigue and post-exertion malaise. Heart rate monitoring is likely to be a safe and effective intervention for managing fatigue and post exertion malaise. Useful resources on pacing and heart rate monitoring are provided below:

Peer Support[edit | edit source]

Peer support involves people sharing knowledge, experience, or practical help with each other, often when living with the same or similar health conditions. Many online Long COVID peer support groups have been established for people living with Long COVID. These are safe spaces for people living with Long COVID to access peer support. Mutual respect and confidentiality is, therefore, requested in these groups. Many of these groups have outputs to share valuable information with allies. Long COVID Physio published blogs with JOSPT highlighting the value of peer support. Long COVID groups include:

References[edit | edit source]

  1. World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it. [Accessed 7 January 2021]
  2. 2.0 2.1 National Institute for Health and Care Excellence (NICE), COVID-19 guideline scope: management of the long-term effects of COVID-19. 2020 [Accessed 7 January 2021].
  3. 3.0 3.1 Perego E, Callard F, Stras L, Melville-Johannesson B, Pope R, Alwan N. Why we need to keep using the patient made term “Long Covid. BMJ Opinion. 2020 Oct 1 [Accessed 7 January 2021].
  4. 4.0 4.1 Callard F, Perego E. How and why patients made Long Covid. Social Science & Medicine. 2020;268:113426.
  5. Nature. Long COVID: let patients help define long-lasting COVID symptoms. 2020 October 7 [Accessed 7 January 2021].
  6. 6.0 6.1 The BMJ. NICE guideline on long covid. 2020 December 23 [Accessed 7 January 2021].
  7. 7.0 7.1 Office for National Statistics. The prevalence of long COVID symptoms and COVID-19 complications. 2020 December 16 [Accessed 7 January 2021].
  8. Long-term effect of coronavirus (Long COVID). NHS, 2021.
  9. E.Perego, F.Callard. Patient-made Long Covid changed COVID-19 (and the production of science, too). SocArXiv, 2021.
  10. Nath A. Long-Haul COVID. Neurology. 2020;95(13):559-560.
  11. Nature. The lasting misery of coronavirus long-haulers. 2020 September 14 [Accessed 7 January 2021].
  12. Baig AM. Chronic COVID Syndrome: Need for An Appropriate Medical Terminology for Long‐COVID and COVID Long‐Haulers. Journal of Medical Virology. 2020;Oct 23.
  13. World Health Organization. Global covid-19 clinical platform case report form (CRF) for post covid condition (Post COVID-19 CRF). 9 Feb 2021.
  14. Goërtz YMJ, Herck MV, Delbressine JM, Vaes AW, Meys R et al. Persistent symptoms 3 months after a SARS-CoV-2 infection: the post-COVID-19 syndrome?. ERJ Open Research. 2020;6(4):1-10.
  15. 15.0 15.1 NHS, National Guidance for Post-COVID Syndrome Assessment Clinics. 2020 November 6 [Accessed 7 January 2021].
  16. Greenhalgh T, Knight M, Buxton M, Husain L. Management of Post-acute Covid-19 in Primary Care. BMJ. 2020;370:1-8.
  17. 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 S.Rajan, K.Khunti, N.Alwan, C.Steves, T.Greenhalgh, N.MacDermott, A.Sagan, M.McKee. In the wake of the pandemic: preparing for Long COVID. World Health Organization regional office for Europe, 2021. Policy Brief 39.
  18. 18.0 18.1 18.2 National Institute of Health Research. Living with Covid19. 2020 October 15 [Accessed 7 January 2021].
  19. Watson S, Namiba A, Lynn V. The language of HIV: a guide for nurses. HIV Nursing. 2019;19(2):BP1-4.
  20. 20.0 20.1 20.2 20.3 National Institute for Health and Care Excellence (NICE). COVID-19 Rapid Guideline: Managing The Long-term Effects of COVID-19. 2020 December 18 [Accessed 8 January 2021].
  21. Public Health England. COVID-19: epidemiology, virology and clinical features. February 18, 2021.
  22. L.Townsend, J.Dowds, K.O'Brien, G.Sheill, AH.Dyer, B.O'Kelly, JP.Hynes, A.Mooney, J.Dunne, CN.Cheallaigh, C.O'Farrelly, NM.Bourke, N.Conlon, I.Martin-Loeches, C.Bergin, P.Nadarajan,C.Bannan. Persistent Poor Health Post-COVID-19 Is Not Associated with Respiratory Complications or Initial Disease Severity. Annals of the American Thoracic Society, 2021.
  23. EL.Graham, JR.Clark, ZS.Orban, PH.Lim, AL.Szymanski, C.Taylor, RM.DiBiase, DT.Jia, R.Balabanov, SU.Ho, A.Batra, EM.Liotta, IJ.Koralnik.Persistent neurologic symptoms and cognitive dysfunction in non‐hospitalized Covid‐19 “long haulers”. Annals of Clinical and Translational Neurology, 2021.
  24. P.Brodin. Immune determinants of COVID-19 disease presentation and severity. Nature Medicine, 2021;27:28–33.
  25. 25.0 25.1 Townsend L, Dyer AH, Jones K, Dunne J, Mooney A, Gaffney F, O'Connor L, Leavy D, O'Brien K, Dowds J, Sugrue JA. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. Plos one. 2020 Nov 9;15(11):e0240784.
  26. M.Augustin, P.Schommers, M.Stecher, F.Dewald, L.Gieselmann, H.Gruell, C.Horn, K.Vanshylla, V.Di Cristanziano, L.Osebold, M.Roventa, T.Riaz, N.Tschernoster, J.Altmueller, L.Rose, S.Salomon, V.Priesner, JC.Luers, C.Albus, S.Rosenkranz, B.Gathof, G.Fätkenheuer, M.Hallek, F.Klein, I.Suárez, C.Lehmann. Recovered not restored: Long-term health consequences after mild COVID-19 in non-hospitalized patients. MedRxiv, 2021.
  27. 27.0 27.1 27.2 JK.Logue, NM.Franko, DJ.McCulloch, D.McDonald, A.Magedson,CR.Wolf, HY.Chu. Sequelae in Adults at 6 Months After COVID-19 Infection. JAMA Netw Open. 2021;4(2):e210830. doi:10.1001/jamanetworkopen.2021.0830
  28. PHOSP-COVID Collaborative Group. Physical, cognitive and mental health impacts of COVID-19 following hospitalisation – a multi-centre prospective cohort study. MedRxiv, 2021.
  29. 29.0 29.1 29.2 29.3 29.4 A.Dennis, M.Wamil, J.Alberts, J.Oben, DJ.Cuthbertson, D.Wootton, M.Crooks, M.Gabbay, M.Brady, L.Hishmeh, E.Attree, M.Heightman, R.Banerjee, A.Banerjee.Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: a prospective, community-based study. BMJ Open 2021;11:e048391. doi: 10.1136/bmjopen-2020-048391
  30. 30.0 30.1 30.2 30.3 30.4 30.5 30.6 30.7 30.8 30.9 Davis HE, Assaf GS, McCorkell L, Wei H, Low RJ, Re’em Y, Redfield S, Austin JP, Akrami A. Characterizing Long COVID in an International Cohort: 7 Months of Symptoms and Their Impact. medRxiv. 2020 Jan 1.
  31. Michelen M, Manoharan L, Elkheir N, Cheng V, Dagens D, Hastie C, O'Hara M, Suett J, Burls A, Foote C, Carson G. Characterising long-term covid-19: a rapid living systematic review. medRxiv. 2020 Jan 1.
  32. 32.0 32.1 N.Ziauddeen, D.Gurdasani, ME.O’Hara, C.Hastie, P.Roderick, G.Yao, NA.Alwan. Characteristics of Long Covid: findings from a social media survey. MedRxiv, 2021.
  33. 33.0 33.1 Carfì A, Bernabei R, Landi F. Persistent symptoms in patients after acute COVID-19. Jama. 2020 Aug 11;324(6):603-5.
  34. 34.0 34.1 Assaf G, Davis H, McCorkell L. Report: What Does COVID-19 Recovery Actually Look Like? An analysis of the prolonged COVID-19 symptoms survey by Patient-Led Research Team. Patient-Led Research [online]. Patient-Led Research. 2020.
  35. Salmon-Ceron D, Slama D, Broucker TD. Clinical, virological and imaging profile in patients with prolonged forms of COVID-19: A cross-sectional study. J Infect. 2020.
  36. 36.0 36.1 36.2 Chaolin Huang, Lixue Huang, Yeming Wang, Xia Li, Lili Ren, Xiaoying Gu, Liang Kang, Li Guo, Min Liu, Xing Zhou, Jianfeng Luo, Zhenghui Huang, Shengjin Tu, Yue Zhao, Li Chen, Decui Xu, Yanping Li, Caihong Li, Lu Peng, Yong Li, Wuxiang Xie, Dan Cui, Lianhan Shang, Guohui Fan, Jiuyang Xu, Geng Wang, Ying Wang, Jingchuan Zhong, Prof Chen Wang, Prof Jianwei Wang, Dingyu Zhang, Prof Bin Cao. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. The Lancet, 2021.
  37. Tabacof L, Tosto-Mancuso J, Wood J, Cortes M, Kontorovich A, McCarthy D, Rizk D, Nasr L, Breyman E, Mohammadi N, Kellner C. Post-acute COVID-19 syndrome negatively impacts health and wellbeing despite less severe acute infection. medRxiv. 2020 Jan 1.
  38. Centers for Disease Control and Prevention. Late Sequelae of COVID-19. 2020 November 13 [Accessed 8 January 2021].
  39. Tenforde MW, Kim SS, Lindsell CJ, Rose EB, Shapiro NI, Files DC, Gibbs KW, Erickson HL, Steingrub JS, Smithline HA, Gong MN. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020. Morbidity and Mortality Weekly Report. 2020 Jul 31;69(30):993.
  40. Nehme M, Braillard O, Alcoba G, Aebischer Perone S, Courvoisier D, Chappuis F, Guessous I. COVID-19 Symptoms: Longitudinal Evolution and Persistence in Outpatient Settings. Annals of internal medicine. 2020 Dec 8.
  41. Sudre CH, Murray B, Varsavsky T, Graham MS, Penfold RS, Bowyer RC, Pujol JC, Klaser K, Antonelli M, Canas LS, Molteni E. Attributes and predictors of Long-COVID. Nature Medicine, 2021.
  42. S.Lopez-Leon, T.Wegman-Ostrosky, C.Perelman, R.Sepulveda, P.Rebolledo, A.Cuapio, S.Villapol. More than 50 Long-term effects of COVID-19: a systematic review and meta-analysis. MedRxiv, 2021.
  43. S.Lopez-Leon, T.Wegman-Ostrosky, C.Perelman, R.Sepulveda, P.A.Rebolledo, A.Cuapio, S.Villapol. More than 50 Long-term effects of COVID-19: a systematic review and meta-analysis. MedRxiv, 2021. https://doi.org/10.1101/2021.01.27.21250617
  44. E.Garrigues, P.Janvier, Y.Kherabi, A.Le Bot, A.Hamon, H.Gouze, L.Doucet, S.Berkani, E.Oliosi, E.Mallart, F.Corre, V.Zarrouk, JD.Moyer, A.Galy, V.Honsel, B.Fantin, Y.Nguyen. Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID-19. Journal of Infection, 2020; 81(6):E4-E6. DOI:https://doi.org/10.1016/j.jinf.2020.08.029
  45. 45.0 45.1 Halpin SJ, McIvor C, Whyatt G, Adams A, Harvey O, McLean L, Walshaw C, Kemp S, Corrado J, Singh R, Collins T. Postdischarge symptoms and rehabilitation needs in survivors of COVID‐19 infection: A cross‐sectional evaluation. Journal of medical virology. 2020 Jul 30.
  46. O.Moreno-Perez, E.Merino, JM.Leon-Ramirez, M.Andres, JM.Ramos, J.Arenas-Jimenez, S.Asensio, R.Sanchez, P.Ruiz-Torregrosa, I.Galan, A.Scholz, A.Amo, P.Gonzalez-delaAleja, V.Boix, J.Gil. Post-acute COVID-19 Syndrome. Incidence and risk factors: a Mediterranean cohort study. Journal of Infection, 2021. DOI:https://doi.org/10.1016/j.jinf.2021.01.004
  47. 47.0 47.1 47.2 47.3 D.Munblit, P.Bobkova, E.Spiridonova, A.Shikhaleva, A.Gamirova, O.Blyuss, NA.Nekliudov, P.Bugaeva, M.Andreeva, A.DunnGalvin, P.Comberiati, C.Apfelbacher, J.Genuneit, S.Avdeev, V.Kapustina, A.Guekht, V.Fomin, AA.Svistunov,  P.Timashev, TM.Drake, S.Wulf Hanson, L.Merson, P.Horby, L.Sigfrid, JT.Scott, MG.Semple, JO.Warner, T.Vos, P.Olliaro, P.Glybochko, D.Butnaru. Risk factors for long-term consequences of COVID-19 in hospitalised adults in Moscow using the ISARIC Global follow-up protocol: StopCOVID cohort study. MedRxiv, 2021. doi: https://doi.org/10.1101/2021.02.17.21251895
  48. 48.0 48.1 D Menges; T.Ballouz; A.Anagnostopoulos; HE.Aschmann; A.Domenghino; JS.Fehr; MA.Puhan. Estimating the burden of post-COVID-19 syndrome in a population-based cohort study of SARS-CoV-2 infected individuals: Implications for healthcare service planning. MedRxiv, 2021. https://doi.org/10.1101/2021.02.27.21252572
  49. B.Osikomaiya, O.Erinoso, KO.Wright, AO.Odusola, B.Thomas, O.Adeyemi, A.Bowale, O.Adejumo, A.Falana, I.Abdus-salam, O.Ogboye, A.Osibogun, A.Abayomi. ‘Long COVID’: persistent COVID-19 symptoms in survivors managed in Lagos State, Nigeria. BMC Infectious Diseases, 2021.
  50. D.Ayoubkhani, K.Khunti, V.Nafilyan, T.Maddox, B.Humberstone, I.Diamond, A.Banerjee. Epidemiology of post-COVID syndrome following hospitalisation with coronavirus: a retrospective cohort study. MedRxiv, 2021. https://doi.org/10.1101/2021.01.15.21249885
  51. 51.0 51.1 51.2 J.Scott, L.Sigfrid, T.Drake, E.Pauley, E.Jesudason, WS.Lim, D.Munblit, C.Hastie, E.Harrison, A.Docherty, P.Olliaro, P.Openshaw, K.Baillie, C.Semple for ISARIC4C Investigators. Symptoms and quality of life following hospitalisation for COVID-19 (Post COVID-19 Syndrome/Long COVID) in the ISARIC WHO Clinical Characterisation Protocol UK: preliminary results. 2021.
  52. D.Buonsenso, D.Munblit, C.De Rose, D.Sinatti, A.Ricchiuto, A.Carfi, P.Valentini. Preliminary Evidence on Long COVID in children. MedRxiv, 2021. https://doi.org/10.1101/2021.01.23.21250375
  53. Office for National Statistics. Coronavirus (COVID-19) Infection Survey, UK Statistical bulletins. [Accessed 8 January 2021]
  54. Office for National Statistics. Updated estimates of the prevalence of long COVID symptoms. Released 21 January 2021. Accessed 21 January 2021.
  55. Hu F, Chen F, Ou Z, Fan Q, Tan X, Wang Y, Pan Y, Ke B, Li L, Guan Y, Mo X. A compromised specific humoral immune response against the SARS-CoV-2 receptor-binding domain is related to viral persistence and periodic shedding in the gastrointestinal tract. Cellular & molecular immunology. 2020 Nov;17(11):1119-25.
  56. Gaebler C, Wang Z, Lorenzi JC, Muecksch F, Finkin S, Tokuyama M, Ladinsky M, Cho A, Jankovic M, Schaefer-Babajew D, Oliveira TY. Evolution of Antibody Immunity to SARS-CoV-2. Nature. 2021 Jan 18.
  57. De Melo GD, Lazarini F, Levallois S, Hautefort C, Michel V, Larrous F, Verillaud B, Aparicio C, Wagner S, Gheusi G, Kergoat L. COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system. bioRxiv. 2020 Jan 1.
  58. Bussani R, Schneider E, Zentilin L, Collesi C, Ali H, Braga L, Volpe MC, Colliva A, Zanconati F, Berlot G, Silvestri F. Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology. EBioMedicine. 2020 Nov 1;61:103104.
  59. Afrin LB, Weinstock LB, Molderings GJ. Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. International Journal of Infectious Diseases. 2020 Nov 1;100:327-32.
  60. Woodruff MC, Ramonell RP, Lee FE, Sanz I. Clinically identifiable autoreactivity is common in severe SARS-CoV-2 Infection. medRxiv. 2020 Jan 1.
  61. BK.Patterson, J.Guevara-Coto, R.Yogendra, E.Francisco, E.Long, A.Pise, H.Rodrigues, P.Parikh, J.Mora, RA.Mora-Rodríguez. Immune-Based Prediction of COVID-19 Severity and Chronicity Decoded Using Machine Learning. BioXriv, 2021. doi: https://doi.org/10.1101/2020.12.16.423122
  62. Miller R, Wentzel AR, Richards GA. COVID-19: NAD+ deficiency may predispose the aged, obese and type2 diabetics to mortality through its effect on SIRT1 activity. Medical Hypotheses. 2020 Nov 1;144:110044.
  63. Vlachoyiannopoulos PG, Magira E, Alexopoulos H, Jahaj E, Theophilopoulou K, Kotanidou A, Tzioufas AG. Autoantibodies related to systemic autoimmune rheumatic diseases in severely ill patients with COVID-19. Annals of the Rheumatic Diseases. 2020 Dec 1;79(12):1661-3.
  64. Wang EY, Mao T, Klein J, Dai Y, Huck JD, Liu F, Zheng NS, Zhou T, Israelow B, Wong P, Lucas C. Diverse Functional Autoantibodies in Patients with COVID-19. medRxiv. 2020 Jan 1.
  65. Shin Jie Yong. Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis. ACS Chem. Neurosci. 2021.https://doi.org/10.1021/acschemneuro.0c00793
  66. E. Guedj, J. Y. Campion, P. Dudouet, E. Kaphan, F. Bregeon, H. Tissot-Dupont, S. Guis, F. Barthelemy, P. Habert, M. Ceccaldi, M. Million, D. Raoult, S. Cammilleri, C. Eldin. 18F-FDG brain PET hypometabolism in patients with long COVID. European Journal of Nuclear Medicine and Molecular Imaging, 2021. https://doi.org/10.1007/s00259-021-05215-4
  67. DW.Nauen, JE.Hooper, M.Stewart, IH.Solomon. Assessing Brain Capillaries in Coronavirus Disease 2019. JAMA Neurology, 2021. doi:10.1001/jamaneurol.2021.0225
  68. M.Boldrini, PD.Canoll, RS. Klein. How COVID-19 Affects the Brain. JAMA Psychiatry, 2021.
  69. V.Mondelli, CM.Pariante. What can neuroimmunology teach us about the symptoms of long-COVID? Oxford Open Immunology, 2021.
  70. J.Remsik, JA.Wilcox, NE.Babady, TA.McMillen, BA.Vachha, NA.Halpern, V.Dhawan, M.Rosenblum, CA.Iacobuzio-Donahue, EK.Avila, B.Santomasso, A.Boire. Inflammatory Leptomeningeal Cytokines Mediate COVID-19 Neurologic Symptoms in Cancer Patients. Cancer Cell 2021, 39; 2: p276-283.2021. DOI: https://doi.org/10.1016/j.ccell.2021.01.007
  71. VO.Puntmann, M.Ludovica Carerj, I.Wieters, M.Fahim, C.Arendt, J.Hoffmann, A.Shchendrygina, F.Escher, M.Vasa-Nicotera, AM.Zeiher, M.Vehreschild, E.Nagel. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020;5(11):1265-1273. doi:10.1001/jamacardio.2020.3557
  72. J.Abbasi. Researchers Investigate What COVID-19 Does to the Heart. JAMA Network, 2021. doi:10.1001/jama.2021.0107
  73. T.Kotecha, DS.Knight, Y.Razvi, K.Kumar, K.Vimalesvaran, G.Thornton, R.Patel, L.Chacko, JT.Brown, C.Coyle, D.Leith, A.Shetye, B.Ariff, R.Bell, G.Captur, M.Coleman, J.Goldring, D.Gopalan, M.Heightman, T.Hillman, L.Howard, M.Jacobs, PS.Jeetley, P.Kanagaratnam, O.Min Kon, LE.Lamb, CH.Manisty, P.Mathurdas, J.Mayet, R.Negus, N.Patel, I.Pierce, G.Russell, A.Wolff, H.Xue, P.Kellman, JC.Moon, TA.Treibel, GD.Cole, M.Fontana. Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance. European Heart Journal, 2021. https://doi.org/10.1093/eurheartj/ehab075
  74. M.Imazio. COVID-19 as a Possible Cause of Myocarditis and Pericarditis. American College of Cardiology, Expert Analysis, Feb 05 2021.
  75. European Society of Cardiology (ECS) Guidance for the Diagnosis and Management of Cardiovascular Disease (CV) during the COVID-19 Pandemic. Last updated on 10 June 2020.
  76. SL.Ramani, J.Samet, CK.Franz, C.Hsieh, CV.Nguyen, C.Horbinski, S.Deshmukh. Musculoskeletal involvement of COVID-19: review of imaging. Skeletal Radiology, 2021. https://doi.org/10.1007/s00256-021-03734-7
  77. 77.0 77.1 Torjesen I. NICE cautions against using graded exercise therapy for patients recovering from covid-19. 2020 July 21 [Accessed 8 January 2021].
  78. E.Ladds, A.Rushforth, S.Wieringa, S.Taylor, C.Rayner, L.Husain, T.Greenhalgh. Developing services for long COVID: lessons from a study of wounded healers. Clinical Medicine 2021 Vol 21, No 1: 59–65. DOI: https://doi.org/10.7861/clinmed.2020-0962
  79. VV.Altiery De Jesús, N.Alwan, F.Callard, Z.Berger. Listening to Long COVID: Epistemic Injustice and COVID-19 morbidity. OSFPrePrints, 2021.
  80. Klok FA, Boon GJ, Barco S, Endres M, Geelhoed JM, Knauss S, Rezek SA, Spruit MA, Vehreschild J, Siegerink B. The Post-COVID-19 Functional Status scale: a tool to measure functional status over time after COVID-19. European Respiratory Journal. 2020 Jul 1;56(1).
  81. Mohamed-Hussein A, Galal I, Saad M, Zayan HE, Abdelsayed M, Moustafa M, Ezzat AR, Helmy R, Abd Elaal H, Aly K, Abderheem S. Post-COVID-19 Functional Status: Relation to age, smoking, hospitalization and comorbidities. medRxiv. 2020 Jan 1.
  82. 82.0 82.1 82.2 D'Cruz RF, Waller MD, Perrin F, Periselneris J, Norton S, Smith LJ, Patrick T, Walder D, Heitmann A, Lee K, Madula R. Chest radiography is a poor predictor of respiratory symptoms and functional impairment in survivors of severe COVID-19 pneumonia. ERJ Open Research. 2020 Jan 1.
  83. FVC.Machado, R.Meys, JM.Delbressine, AW.Vaes, YMJ.Goërtz, M.van Herck, S.Houben-Wilke, GJAM.Boon, S.Barco, C.Burtin, A.van 't Hul, R.Posthuma, FME.Franssen, Y.Spies, H.Vijlbrief, F.Pitta, SA.Rezek, DJA.Janssen, B.Siegerink, FA.Klok, MA.Spruit. Construct validity of the Post-COVID-19 Functional Status Scale in adult subjects with COVID-19. Health Qual Life Outcomes. 2021 Feb 3;19(1):40. doi: 10.1186/s12955-021-01691-2.
  84. Sivan M, Halpin S, Gee J. Assessing long-term rehabilitation needs in COVID-19 survivors using a telephone screening tool (C19-YRS tool). Advances in Clinical Neurosciences and Rehabilitation. 2020 Jun 29;19(4):14-7.
  85. Sivan M. Remote assessment for identifying COVID-19 post-acute care needs. Aging Clinical and Experimental Research. 2020 Oct;32(10):2167-8.
  86. Tong A, Elliott JH, Azevedo LC, Baumgart A, Bersten A, Cervantes L, Chew DP, Cho Y, Cooper T, Crowe S, Douglas IS. Core outcomes set for trials in people with coronavirus disease 2019. Critical care medicine. 2020 Nov;48(11):1622.
  87. A Tong, A Baumgart, Evangelidis N et al. Core Outcome Measures for Trials in People With Coronavirus Disease 2019: Respiratory Failure, Multiorgan Failure, Shortness of Breath, and Recovery. Critical Care Medicine, 2021; 49(3): 503-516. DOI: 10.1097/CCM.0000000000004817
  88. 88.0 88.1 Arnold DT, Hamilton FW, Milne A, Morley AJ, Viner J, Attwood M, Noel A, Gunning S, Hatrick J, Hamilton S, Elvers KT. Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from a prospective UK cohort. Thorax. 2020 Dec 3.
  89. R.Núñez-Cortés, G.Rivera-Lillo, M.Arias-Campoverde, D. Soto-García, R.García-Palomera, R.Torres-Castro. Use of sit-to-stand test to assess the physical capacity and exertional desaturation in patients post COVID-19. Chronic Respiratory Disease, 2021.https://doi.org/10.1177/1479973121999205
  90. Raman B, Cassar MP, Tunnicliffe EM, Filippini N, Griffanti L, Alfaro-Almagro F, Okell T, Sheerin F, Xie C, Mahmod M, Mózes FE. Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge. medRxiv. 2020 Jan 1.
  91. Daher A, Balfanz P, Cornelissen C, Müller A, Bergs I, Marx N, Müller-Wieland D, Hartmann B, Dreher M, Müller T. Follow up of patients with severe coronavirus disease 2019 (COVID-19): Pulmonary and extrapulmonary disease sequelae. Respiratory medicine. 2020 Nov 1;174:106197.
  92. Huang Y, Tan C, Wu J, Chen M, Wang Z, Luo L et al. Impact of Coronavirus Disease 2019 on Pulmonary Function in Early Convalescence Phase. Respiratory Research. 2020;21:163.
  93. Sonnweber T, Boehm A, Sahanic S, Pizzini A, Aichner M, Sonnweber B, Kurz K, Koppelstätter S, Haschka D, Petzer V, Hilbe R. Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients’ performance: a prospective observational cohort study. Respiratory research. 2020 Dec;21(1):1-9.
  94. Savarraj JP, Burkett AB, Hinds SN, Paz AS, Assing AR, Juneja S, Colpo GD, Torres LF, Gusdon AM, McCullough L, Choi HA. Three-month outcomes in hospitalized COVID-19 patients. medRxiv. 2020 Jan 1.
  95. 95.0 95.1 Holtzman CS, Bhatia S, Cotler J, Jason LA. Assessment of post-exertional malaise (PEM) in patients with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS): a patient-driven survey. Diagnostics. 2019 Mar;9(1):26.
  96. 96.0 96.1 Jason LA, Sunnquist M. The Development of the DePaul Symptom Questionnaire: Original, Expanded, Brief, and Pediatric Versions. Frontiers in pediatrics. 2018 Nov 6;6:330.
  97. 97.0 97.1 NICE. NICE draft guidance addresses the continuing debate about the best approach to the diagnosis and management of ME/CFS. 2020 November 10 [Accessed 8 January 2020].
  98. J.Wise. Long covid: WHO calls on countries to offer patients more rehabilitation. BMJ 2021;372:n405. doi: https://doi.org/10.1136/bmj.n405
  99. National Institute for Health and Care Excellence (NICE). Myalgic encephalomyelitis (or encephalopathy) /chronic fatigue syndrome: diagnosis and management, In development [GID-NG10091] Expected publication date:
  100. Dialogues for a Neglected Illness (Dialogues for ME/CFS). Graded Exercise Therapy. [Accessed 8 January 2021]
  101. Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powles AP, Speight N, Vallings R, Bateman L. Myalgic encephalomyelitis: international consensus criteria. Journal of internal medicine. 2011 Oct;270(4):327-38.
  102. Stussman B, Williams A, Snow J, Gavin A, Scott R, Nath A, Walitt B. Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Frontiers in Neurology. 2020 Sep 18;11:1025.
  103. Stephens C. MEA Summary Review: Assessing PEM (Post-exertional malaise). The ME Association. 2019 March 25 [Accessed 8 January 2021].
  104. Chu L, Valencia IJ, Garvert DW, Montoya JG. Deconstructing post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: A patient-centered, cross-sectional survey. PloS one. 2018 Jun 1;13(6):e0197811.
  105. Phelan D, Kim JH, Elliott MD, Wasfy MM, Cremer P, Johri AM et al. Screening of Potential Cardiac Involvemenappt in Competitive Athletes Recovering from COVID-19: An Expert Consensus Statement. JACC: Cardiovascular Imaging. 2020;13(12):2635-2652.
  106. National Institute for Health Research (NIHR). Rehabilitation Exercise and psycholoGical support After covid-19 InfectioN (REGAIN). [Accessed 8 January 2021]

.