Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection

Liam Townsend, Adam H Dyer, Karen Jones, Jean Dunne, Aoife Mooney, Fiona Gaffney, Laura O'Connor, Deirdre Leavy, Kate O'Brien, Joanne Dowds, Jamie A Sugrue, David Hopkins, Ignacio Martin-Loeches, Cliona Ni Cheallaigh, Parthiban Nadarajan, Anne Marie McLaughlin, Nollaig M Bourke, Colm Bergin, Cliona O'Farrelly, Ciaran Bannan, Niall Conlon, Liam Townsend, Adam H Dyer, Karen Jones, Jean Dunne, Aoife Mooney, Fiona Gaffney, Laura O'Connor, Deirdre Leavy, Kate O'Brien, Joanne Dowds, Jamie A Sugrue, David Hopkins, Ignacio Martin-Loeches, Cliona Ni Cheallaigh, Parthiban Nadarajan, Anne Marie McLaughlin, Nollaig M Bourke, Colm Bergin, Cliona O'Farrelly, Ciaran Bannan, Niall Conlon

Abstract

Fatigue is a common symptom in those presenting with symptomatic COVID-19 infection. However, it is unknown if COVID-19 results in persistent fatigue in those recovered from acute infection. We examined the prevalence of fatigue in individuals recovered from the acute phase of COVID-19 illness using the Chalder Fatigue Score (CFQ-11). We further examined potential predictors of fatigue following COVID-19 infection, evaluating indicators of COVID-19 severity, markers of peripheral immune activation and circulating pro-inflammatory cytokines. Of 128 participants (49.5 ± 15 years; 54% female), more than half reported persistent fatigue (67/128; 52.3%) at median of 10 weeks after initial COVID-19 symptoms. There was no association between COVID-19 severity (need for inpatient admission, supplemental oxygen or critical care) and fatigue following COVID-19. Additionally, there was no association between routine laboratory markers of inflammation and cell turnover (leukocyte, neutrophil or lymphocyte counts, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, C-reactive protein) or pro-inflammatory molecules (IL-6 or sCD25) and fatigue post COVID-19. Female gender and those with a pre-existing diagnosis of depression/anxiety were over-represented in those with fatigue. Our findings demonstrate a significant burden of post-viral fatigue in individuals with previous SARS-CoV-2 infection after the acute phase of COVID-19 illness. This study highlights the importance of assessing those recovering from COVID-19 for symptoms of severe fatigue, irrespective of severity of initial illness, and may identify a group worthy of further study and early intervention.

Conflict of interest statement

The authors have declared that no competing interests exist.

References

    1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. 10.1016/S0140-6736(20)30183-5
    1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–9. 10.1001/jama.2020.1585
    1. Xu X-W, Wu X-X, Jiang X-G, Xu K-J, Ying L-J, Ma C-L, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ. 2020;368.
    1. Zhang J-j, Dong X, Cao Y-y, Yuan Y-d, Yang Y-b, Yan Y-q, et al. Clinical characteristics of 140 patients infected with SARS‐CoV‐2 in Wuhan, China. Allergy. 2020. 10.1111/all.14238
    1. Tian S, Hu N, Lou J, Chen K, Kang X, Xiang Z, et al. Characteristics of COVID-19 infection in Beijing. J Infect. 2020.
    1. Zhu J, Ji P, Pang J, Zhong Z, Li H, He C, et al. Clinical characteristics of 3,062 COVID‐19 patients: a meta‐analysis. J Med Virol. 2020.
    1. Zhu J, Zhong Z, Ji P, Li H, Li B, Pang J, et al. Clinicopathological characteristics of 8697 patients with COVID-19 in China: a meta-analysis. Fam Med Community Health. 2020;8(2). 10.1136/fmch-2020-000406
    1. Vaira LA, Hopkins C, Salzano G, Petrocelli M, Melis A, Cucurullo M, et al. Olfactory and gustatory function impairment in COVID‐19 patients: Italian objective multicenter‐study. Head Neck. 2020. 10.1002/hed.26269
    1. Kerr C, Hughes G, Mckenna L, Bergin C. Prevalence of smell and taste dysfunction in a cohort of CoVID19 outpatients managed through remote consultation from a large urban teaching hospital in Dublin, Ireland. IPIP. 2020:100076.
    1. Wilson C. Concern coronavirus may trigger post-viral fatigue syndromes. New Scientist (1971). 2020;246(3278):10 10.1016/S0262-4079(20)30746-6
    1. Bansal A, Bradley A, Bishop K, Kiani-Alikhan S, Ford B. Chronic fatigue syndrome, the immune system and viral infection. Brain Behav Immun. 2012;26(1):24–31. 10.1016/j.bbi.2011.06.016
    1. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020. 10.1093/cid/ciaa248
    1. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5). 10.1172/JCI137244
    1. Zhou Y, Fu B, Zheng X, Wang D, Zhao C. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. National Science Review. 2020.
    1. Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol. 2011;11(1):37 10.1186/1471-2377-11-37
    1. Lam MH-B, Wing Y-K, Yu MW-M, Leung C-M, Ma RC, Kong AP, et al. Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: long-term follow-up. Arch Intern Med. 2009;169(22):2142–7. 10.1001/archinternmed.2009.384
    1. Lee SH, Shin H-S, Park HY, Kim JL, Lee JJ, Lee H, et al. Depression as a mediator of chronic fatigue and post-traumatic stress symptoms in Middle East respiratory syndrome survivors. Psychiatry Investig. 2019;16(1):59 10.30773/pi.2018.10.22.3
    1. Katz BZ, Collin SM, Murphy G, Moss-Morris R, Wyller VB, Wensaas K-A, et al. The international collaborative on fatigue following infection (COFFI). Fatigue: biomedicine, health & behavior. 2018;6(2):106–21. 10.1080/21641846.2018.1426086
    1. Katz BZ, Shiraishi Y, Mears CJ, Binns HJ, Taylor R. Chronic fatigue syndrome after infectious mononucleosis in adolescents. Pediatrics. 2009;124(1):189–93. 10.1542/peds.2008-1879
    1. Galbraith S, Cameron B, Li H, Lau D, Vollmer-Conna U, Lloyd AR. Peripheral blood gene expression in postinfective fatigue syndrome following from three different triggering infections. J Infect Dis. 2011;204(10):1632–40. 10.1093/infdis/jir612
    1. Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006;333(7568):575 10.1136/
    1. De Vito A, Geremia N, Mameli SM, Fiore V, Serra PA, Rocchitta G, et al. Epidemiology, clinical aspects, laboratory diagnosis and treatment of rickettsial diseases in the mediterranean area during COVID-19 pandemic: a review of the literature. Mediterr J Hematol Infect Dis. 2020;12(1). 10.4084/MJHID.2020.056
    1. Eymard D, Lebel F, Miller M, Turgeon F. Human herpesvirus 6 and chronic fatigue syndrome. Can J Infect Dis. 1993;4 10.1155/1993/414602
    1. Barroso J, Leserman J, Harmon JL, Hammill B, Pence BW. Fatigue in HIV-infected people: a three-year observational study. J Pain Symptom Manage. 2015;50(1):69–79. 10.1016/j.jpainsymman.2015.02.006
    1. Kruesi MJ, Dale J, Straus SE. Psychiatric diagnoses in patients who have chronic fatigue syndrome. J Clin Psychiatry. 1989.
    1. Taerk GS, Toner BB, Salit IE, Garfinkel PE, Ozersky S. Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). The International Journal of Psychiatry in Medicine. 1988;17(1):49–56.
    1. Cope H, Mann A, David A, Pelosi A. Predictors of chronic" postviral" fatigue. The Lancet. 1994;344(8926):864–8. 10.1016/s0140-6736(94)92833-9
    1. Klimas NG, Broderick G, Fletcher MA. Biomarkers for chronic fatigue. Brain Behav Immun. 2012;26(8):1202–10. 10.1016/j.bbi.2012.06.006
    1. Montoya JG, Holmes TH, Anderson JN, Maecker HT, Rosenberg-Hasson Y, Valencia IJ, et al. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci U S A. 2017;114(34):E7150–E8. 10.1073/pnas.1710519114
    1. Natelson BH, Haghighi MH, Ponzio NM. Evidence for the presence of immune dysfunction in chronic fatigue syndrome. Clin Diagn Lab Immunol. 2002;9(4):747–52. 10.1128/cdli.9.4.747-752.2002
    1. Mihaylova I, DeRuyter M, Rummens L-L, Bosmans E, Maes M. Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells. Neuroendocrinology Letters. 2007;28(4):477–83.
    1. Robertson M, Schacterle R, Mackin G, Wilson S, Bloomingdale K, Ritz J, et al. Lymphocyte subset differences in patients with chronic fatigue syndrome, multiple sclerosis and major depression. Clin Exp Immunol. 2005;141(2):326–32. 10.1111/j.1365-2249.2005.02833.x
    1. Brenu EW, Broadley S, Nguyen T, Johnston S, Ramos S, Staines D, et al. A preliminary comparative assessment of the role of CD8+ T cells in chronic fatigue syndrome/Myalgic encephalomyelitis and multiple sclerosis. J Immunol Res. 2016;2016 10.1155/2016/9064529
    1. Bradley A, Ford B, Bansal A. Altered functional B cell subset populations in patients with chronic fatigue syndrome compared to healthy controls. Clin Exp Immunol. 2013;172(1):73–80. 10.1111/cei.12043
    1. Butler S, Chalder T, Ron M, Wessely S. Cognitive behaviour therapy in chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 1991;54(2):153–8. 10.1136/jnnp.54.2.153
    1. Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, et al. Development of a fatigue scale. J Psychosom Res. 1993;37(2):147–53. 10.1016/0022-3999(93)90081-p
    1. Jackson C. The Chalder fatigue scale (CFQ 11). Occup Med. 2015;65(1):86–. 10.1093/occmed/kqu168
    1. Morriss R, Wearden A, Mullis R. Exploring the validity of the Chalder Fatigue scale in chronic fatigue syndrome. J Psychosom Res. 1998;45(5):411–7. 10.1016/s0022-3999(98)00022-1
    1. Loge JH, Ekeberg Ø, Kaasa S. Fatigue in the general Norwegian population: normative data and associations. J Psychosom Res. 1998;45(1):53–65. 10.1016/s0022-3999(97)00291-2
    1. Jackson C. The general health questionnaire. Occup Med. 2007;57(1):79–.
    1. Rockwood K, Song X, MacKnight C, Bergman H, Hogan DB, McDowell I, et al. A global clinical measure of fitness and frailty in elderly people. Can Med Assoc J. 2005;173(5):489–95.
    1. Association WM. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Bull World Health Organ. 2001;79(4):373
    1. Koopmans P, Bakhtali R, Katan A, Groothoff J, Roelen C. Return to work following sickness absence due to infectious mononucleosis. Occup Med. 2010;60(4):249–54. 10.1093/occmed/kqq061
    1. Assessment RR. Coronavirus disease 2019 (COVID-19) in the EU/EEA and the UK–ninth update. European Centre for Disease Prevention and Control: Stockholm; 2020.
    1. Heneghan C, Oke J, Jefferson T. COVID-19 How many Healthcare workers are infected? 2020. 17 April 2020 [cited 2020 27 April].
    1. Hunter E, Price DA, Murphy E, van der Loeff IS, Baker KF, Lendrem D, et al. First experience of COVID-19 screening of health-care workers in England. The Lancet. 2020;395(10234):e77–e8. 10.1016/S0140-6736(20)30970-3
    1. Moreh E, Jacobs JM, Stessman J. Fatigue, function, and mortality in older adults. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences. 2010;65(8):887–95.
    1. Kokubun K, Nemoto K, Oka H, Fukuda H, Yamakawa Y, Watanabe Y. Association of fatigue and stress with gray matter volume. Front Behav Neurosci. 2018;12:154 10.3389/fnbeh.2018.00154
    1. Kim B-H, Namkoong K, Kim J-J, Lee S, Yoon KJ, Choi M, et al. Altered resting-state functional connectivity in women with chronic fatigue syndrome. Psychiatry Res Neuroimaging. 2015;234(3):292–7. 10.1016/j.pscychresns.2015.10.014
    1. Rimes KA, Chalder T. The Beliefs about Emotions Scale: validity, reliability and sensitivity to change. J Psychosom Res. 2010;68(3):285–92. 10.1016/j.jpsychores.2009.09.014
    1. Coetzee B, Loades M, Du Toit S, Read R, Kagee A. Fatigue among South African adolescents living with HIV: is the Chalder Fatigue Questionnaire a suitable measure and how common is fatigue? Vulnerable Children and Youth Studies. 2018;13(4):305–16. 10.1080/17450128.2018.1510147
    1. Jeon HO, Kim J, Kim O. Factors affecting depressive symptoms in employed hemodialysis patients with chronic renal failure. Psychol Health Med. 2019:1–10. 10.1080/13548506.2019.1702218
    1. Takakura S, Oka T, Sudo N. Changes in circulating microRNA after recumbent isometric yoga practice by patients with myalgic encephalomyelitis/chronic fatigue syndrome: an explorative pilot study. Biopsychosoc Med. 2019;13(1):29 10.1186/s13030-019-0171-2
    1. Stubhaug B, Lier HO, Aßmus J, Rongve A, Kvale G. A 4-day Mindfulness-Based cognitive behavioral intervention program for CFS/ME. an open study, with 1-year follow-up. Front Psychiatry. 2018;9:720 10.3389/fpsyt.2018.00720
    1. Herridge MS, Cheung AM, Tansey CM, Matte-Martyn A, Diaz-Granados N, Al-Saidi F, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med. 2003;348(8):683–93. 10.1056/NEJMoa022450
    1. Faro M, Sàez-Francás N, Castro-Marrero J, Aliste L, de Sevilla TF, Alegre J. Gender differences in chronic fatigue syndrome. Reumatología clínica (English edition). 2016;12(2):72–7. 10.1016/j.reuma.2015.05.007
    1. Cluff LE. Medical aspects of delayed convalescence. Rev Infect Dis. 1991;13(Supplement_1):S138–S40. 10.1093/clinids/13.supplement_1.s138
    1. Komaroff AL, Cho TA, editors. Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol; 2011: © Thieme Medical Publishers.
    1. Prins J. B., Meer WW van der, & Bleijenberg G.(2006). Chronic fatigue syndrome. The Lancet. 367:346–55.
    1. He X, Lau EH, Wu P, Deng X, Wang J, Hao X, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med. 2020;26(5):672–5.
    1. Lee N-Y, Li C-W, Tsai H-P, Chen P-L, Syue L-S, Li M-C, et al. A case of COVID-19 and pneumonia returning from Macau in Taiwan: Clinical course and anti-SARS-CoV-2 IgG dynamic. J Microbiol Immunol Infect. 2020.
    1. Ling Y, Xu S-B, Lin Y-X, Tian D, Zhu Z-Q, Dai F-H, et al. Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients. Chin Med J. 2020.
    1. Jason L, Benton M, Torres-Harding S, Muldowney K. The impact of energy modulation on physical functioning and fatigue severity among patients with ME/CFS. Patient Educ Couns. 2009;77(2):237–41. 10.1016/j.pec.2009.02.015
    1. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet. 2011;377(9768):823–36.
    1. Galeoto G, Sansoni J, Valenti D, Mollica R, Valente D, Parente M, et al. The effect of physiotherapy on fatigue and physical functioning in chronic fatigue syndrome patients: a systematic review. La Clinica Terapeutica. 2018;169(4):e184–e8. 10.7417/T.2018.2076
    1. Vink M, Vink-Niese F. Work Rehabilitation and Medical Retirement for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. A Review and Appraisal of Diagnostic Strategies. Diagnostics. 2019;9(4):124.

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