Long Term Health Sequelae of COVID-19: A Review
Abstract
The outbreak of Coronavirus disease 19 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a pandemic by World Health Organization (WHO) on 11th March, 2020. COVID-19 infection predominantly manifests as pulmonary symptoms that may progress to acute respiratory distress syndrome. The data on extra-pulmonary manifestations of acute COVID-19 are available. Most patients who have COVID-19 recover well within months. Currently, more than 50 million people have recovered globally. Many reports of patients with persistent severe symptoms and significant end-organ damage after SARS-CoV-2 infection have also been observed. As COVID-19 is a relatively new disease, future sequelae aren’t well established. Major adverse outcomes were found to affect different body systems: respiratory system (lung fibrosis and pulmonary thromboembolism), cardiovascular system (cardiomyopathy), and neurological system (sensory dysfunction and stroke). Mental health of COVID-19 patients were also found to be adversely affected. This review describes the effects of SARS-CoV-2 taking into account the previous experiences with SARS-CoV-2 and the Middle East Respiratory Syndrome (MERS) coronavirus that caused SARS in 2003 and MERS in 2012 respectively. This review aims to update on the long-term sequelae of SARS-CoV-2 infection and highlight the necessity for patient monitoring following the acute stage of infection with SARS-CoV-2 to provide ground for the prevention, diagnosis, and management of these potential long-term sequelae and to complete the natural history of COVID-19.
How to cite this article:
Kumar N, Wasnik D, Vardhan H, Daga MK. Long Term Health Sequelae of COVID-19: A Review. J Adv Res Med.2021;8(1):9-18.
DOI: https://doi.org/10.24321/2349.7181.202102
References
Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet.
;395(10223):470-3. [PubMed] [Google Scholar]
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen
KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng
P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS, China Medical Treatment
Expert Group for COVID-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med.
;382(18):1708-20. [PubMed] [Google Scholar]
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Tao
H, Zhou H, Hu Z, Zhou W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, Wang D, Xu
W, Holmes EC, Gao GF, Wu G, Chen W, Shi W, Tan W. Genomic characterisation and epidemiology of 2019
novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565-74.
[Google Scholar]
Calabrese F, Pezzuto F, Fortarezza F, Hofman P, Kern I, Panizo A, Thusen J, Timofeev S, Gorkiewicz G, Lunardi
F. Pulmonary pathology and COVID-19: Lessons from autopsy. The experience of European Pulmonary
Pathologists. Virchows Arch. 2020 Sep;477(3):359-72. [PubMed] [Google Scholar]
Tian S, Xiong Y, Liu H, Niu Li, Guo J, Liao M, Xiao S. Pathological study of the 2019 novel coronavirus
disease (COVID-19) through post-mortem core biopsies. Mod Pathol. 2020;33(6):1007-14. [PubMed] [Google
Scholar]
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome.
Lancet Respir Med. 2020;8(4):420-2. [PubMed] [Google Scholar]
NHS England [Internet]. Aftercare needs of inpatients recovering from COVID-19. Jun 2020. Available from:
https://www.cambscommunityservices.nhs.uk/docs/default-source/luton-adults-general/c0388_after_care_
needs_of_inpatients_recovering_from_covid-19_5_june_2020.pdf.
Zhao YM, Shang YM, Song WB, Li QQ, Xie H, Xu QF, Jia JL, Li LM, Mao HL, Zhou XM, Luo H, Gao YF, Xu AG.
Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors
three months after recovery. EClinicalMedicine. 2020;25:100463. [PubMed] [Google Scholar]
Huang Y, Tan C, Wu J, Chen M, Wang Z, Luo L, Zhou X, Liu X, Huang X, Yuan S, Chen C, Gao F, Huang J, Shan H,
Liu J. Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase. Respir Res.
;21(1):163. [PubMed] [Google Scholar]
Liu X, Zhou H, Zhou Y, Wu X, Zhao Y, Lu Y, Tan W, Yuan M, Ding X, Zou J, Li R, Liu H, Ewing RM, Hu Y, Nie H,
Wang Y. Risk factors associated with disease severity and length of hospital stay in COVID-19 patients. J
Infect. 2020;81(1):95-7. [PubMed] [Google Scholar]
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S,
Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in
Wuhan, China: a retrospective cohort study. Lancet.2020;395(10229):1054-62. [PubMed] [Google Scholar]
Pan F, Ye T, Sun P, Gui S, Liang B, Li L, Zheng D, Wang J, Hesketh RL, Yang L, Zheng C. Time Course of Lung
Changes at Chest CT during Recovery from Coronavirus Disease 2019 (COVID-19). Radiology. 2020;295(3):715-
[PubMed] [Google Scholar]
Liu C, Ye L, Xia R, Zheng X, Yuan C, Wang Z, Lin R, Shi D, Gao Y, Yao J, Sun Q, Wang X, Jin M. Chest Computed
Tomography and clinical follow-up of discharged patients with COVID-19 in Wenzhou City, Zhejiang,
China. Ann Am Thorac Soc. 2020;17(10):1231-7.[PubMed] [Google Scholar]
Ojo AS, Balogun SA, Williams OT, Ojo OS. Pulmonary Fibrosis in COVID-19 Survivors: Predictive Factors and
Risk Reduction Strategies. Pulm Med. 2020;5:1-10. [PubMed] [Google Scholar]
Zuo W, Zhao X, Chen YG. SARS coronavirus and lung fibrosis. In: Lal SK, editor. Molecular biology of the
SARS-coronavirus. Berlin and Heidelberg: Springer; 2010. p. 247-58. [Google Scholar].
Collins BF, Raghu G. Antifibrotic therapy for fibrotic lung disease beyond idiopathic pulmonary fibrosis.
Eur Respir Rev. 2019;28(153):19-23. [PubMed] [Google Scholar]
Li Y, Li H, Liu S, Pan P, Su X, Tan H, Wu D, Zhang L, Song C, Dai M, Li Q, Mao Z, Long Y, Hu Y, Hu C.
Pirfenidone ameliorates lipopolysaccharide-induced pulmonary inflammation and fibrosis by blocking NLRP3
inflammasome activation. Mol Immunol. 2018;99:134-44. [PubMed] [Google Scholar]
Chen JY, Qiao K, Liu F, Wu B, Xu X, Jiao GQ, Lu RG, Li HX, Zhao J, Huang J, Yang Y, Lu XJ, Li JS, Jiang SY, Wang
DP, Hu CX, Wang GL, Huang DX, Jiao GH, Wei D, Ye SG, Huang JA, Zhou L, Zhang XQ, He JX. Lung transplantation
as therapeutic option in acute respiratory distress syndrome for coronavirus disease 2019-related
pulmonary fibrosis. Chin Med J (Engl). 2020 Jun 20;133(12):1390-6. [PubMed] [Google Scholar]
Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, Gong W, Liu X, Liang J, Zhao Q, Huang H, Yang B, Huang C. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol.
;5(7):802-10. [PubMed] [Google Scholar]
Wilson JG, Liu KD, Zhuo H, Caballero L, McMilan M, Fang X, Cosgrove K, Vojnik R, Calfee CS, Lee JW, Rogers
AJ, Levitt J, Wiener-Kronish J, Bajwa EK, Leavitt A, McKenna D, Thompson BT, Matthay MA. Mesenchymal
stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med.2015;3(1):24-32.
[PubMed] [Google Scholar]
Mishra GP, Mulani J. Corticosteroids for COVID-19: the search for an optimum duration of therapy. Lancet
Respir Med. 2021 Jan;9(1):e8. [PubMed] [Google Scholar]
Arastehfar A, Carvalho A, van de Veerdonk FL, Jenks JD, Koehler P, Krause R, Cornely OA, Perlin DS, Lass-
Florl C, Hoenigl M. COVID-19 associated pulmonary aspergillosis (CAPA)-from immunology to treatment. J
Fungi (Basel). 2020;6(2):91. [PubMed] [Google Scholar]
Chennamchetty VK, Adimulapu S, Kola BP, Padua MD, Ambika C, Verma MK, Rao MVR. Post-COVID pulmonary
mucormycosis- A case report. IP Indian J Immunol Respir Med. 2021;6(1):62-6. [Google Scholar]
Mehta S, Pandey A. Rhino-Orbital Mucormycosis Associated With COVID-19. Cureus. 2020;12(9):10726.
[Google Scholar]
Kumar N, Kumar S, Vardhan H, Lakhtakia L, Daga MK. Cardiovascular Manifestations of SARS CoV-2: A Review.
J Adv Res Med. 2020;7(2):1-10. [Google Scholar]
Inciardi RM, Lupi L, Zaccone G, Italia L, Raffo M, Tomasoni D, Cani DS, Cerini M, Farina D, Gavazzi E,
Maroldi R, Adamo M, Ammirati E, Sinagra G, Lombardi CM, Metra M. Cardiac involvement in a patient with
coronavirus disease 2019 (COVIDâ€19). JAMA Cardiol.2020;5(7):819-24. [PubMed] [Google Scholar]
Wu Q, Zhou L, Sun X, Yan Z, Hu C, Wu J, Xu L, Li X, Liu H, Yin P, Li K, Zhao J, Li Y, Wang X, Li Y, Zhang Q, Xu G, Chen H. Altered lipid metabolism in recovered SARS patients twelve years after infection. Sci Rep. 2017;7(1):9110.
[PubMed] [Google Scholar]
Yu CM, Wong RS, Wu EB, Kong SL, Wong J, Yip GWK, Soo YOY, Chiu MLS, Chan YS, Hui D, Lee N, Wu A,
Leung CB, Sung JJY. Cardiovascular complications of severe acute respiratory syndrome. Postgrad Med J.
;82(964):140â€4. [PubMed] [Google Scholar]
Vaira LA, Salzano G, Deiana G, Salzano FA, Riu GD. In Response to: In Reference to Anosmia and Ageusia:
Common Findings in COVID-19 Patients. Laryngoscope.2020;30(10):1002. [Google Scholar]
Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, Kneen R, Defres S, Sejvar J, Solomon T.
Neurological associations of COVID-19. Lancet Neurol.2020 Sep;19(9):767-83. [PubMed] [Google Scholar]
Pezzini A, Padovani A. Lifting the mask on neurological manifestations of COVID-19. Nat Rev Neurol.
;16(11):636-44. [PubMed] [Google Scholar]
Tsai LK, Hsieh ST, Chang YC. Neurological manifestations in severe acute respiratory syndrome. Acta Neurol
Taiwan. 2005;14(3):113-9. [PubMed] [Google Scholar]
Barrantes FJ. Central nervous system targets and routes for SARS-CoV-2: Current views and new hypotheses.
ACS Chem Neurosci. 2020;11(18):2793-803. [PubMed] [Google Scholar]
Bilinska K, Jakubowska P, Von Bartheld CS, Butowt R. Expression of the SARS-CoV-2 entry proteins, ACE2
and TMPRSS2, in cells of the olfactory epithelium: Identification of cell types and trends with age. ACS
Chem Neurosci. 2020;11(11):1555-62. [PubMed] [Google Scholar]
Calderón-Garciduenas L, Torres-Jardon R, Franco-Lira M, Kulesza R, Gonzalez-Maciel A, Reynoso-Robles R,
Brito-Aguilar R, Garcia-Arreola B, Revueltas-Ficachi P, Barrera-Velazquez JA, Gracia-Alonso G, Garcia-Rojas
E, Mukherjee PS, Delgado-Chavez R. Environmental nanoparticles, SARS-CoV-2 brain involvement, and
potential acceleration of Alzheimer’s and Parkinson’s diseases in young urbanites exposed to air pollution. J
Alzheimers Dis. 2020;78(2):479-503. [PubMed] [Google Scholar]
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brossewon F, Feinstein DL, Jacobs AH, Wyss-Coray T,
Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J,
Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot
S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock
DT, Kummer MP. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388-405. [PubMed]
[Google Scholar]
Sulzer D, Antonini A, Leta V, Nordvig A, Smeyne RJ, Goldman JE, Al-Dalahmah O, Zecca L, Sette A, Bubacco
L, Meucci O, Moro E, Harms AS, Xu Y, Fahn S, Chaudhuri KR. COVID-19 and possible links with Parkinson’s
disease and parkinsonism: From bench to bedside. NPJ Parkinsons Dis. 2020;6:18. [PubMed] [Google Scholar]
Kempuraj D, Selvakumar GP, Ahmed ME, Raikwar SP, Thangavel R, Khan A, Zaheer SA, Iyer SS, Burton C,
James D, Zaheer A. COVID-19, mast cells, cytokine storm, psychological stress, and neuroinflammation.
Neuroscientist. 2020;26(5-6):402-14. [PubMed] [Google Scholar]
Palao M, Fernández-DÃaz E, Gracia-Gil J, Romero-Sanchez CM, Diaz-Maroto I, Segura T. Multiple sclerosis
following SARS-CoV-2 infection. Mult Scler Relat Disord. 2020;45:102377. [PubMed] [Google Scholar]
Arbour N, Day R, Newcombe J, Talbot PJ. Neuroinvasion by human respiratory
coronaviruses. J Virol.2000;74(19):8913-21. [PubMed] [Google Scholar]
Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, Zandi MS, Lewis G, David AS. Psychiatric
and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review
and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry. 2020;7(7):611-27.
[PubMed] [Google Scholar]
Brooks SK, Webster RK, Smith LE, Woodland L, Wessely S, Greenberg N, Rubin GJ. The psychological impact of
quarantine and how to reduce it: rapid review of the evidence. Lancet. 2020;395(10227):912â€20. [PubMed]
[Google Scholar]
Galea S, Merchant RM, Lurie N. The mental health consequences of COVID-19 and physical distancing: the
need for prevention and early intervention. JAMA Intern Med. 2020;180(6):817-18. [PubMed] [Google Scholar]
Carvalho PMM, Moreira MM, Oliveira MNA, Landim JMM, Neto MLR. The psychiatric impact of the novel
coronavirus outbreak. Psychiatry Res. 2020;286:112902.[PubMed] [Google Scholar]
Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol. 2010;47(3):193-9. [PubMed] [Google Scholar]
Wheatland R. Molecular mimicry of ACTH in SARS—implications for corticosteroid treatment and
prophylaxis. Med Hypotheses. 2004;63(5):855-62. [PubMed] [Google Scholar]
Leow MKS, Kwek DSK, Ng AWK, Ong KC, Kaw GJL, Lee LSU. Hypocortisolism in survivors of severe
acute respiratory syndrome (SARS). Clin Endocrinol.2005;63(2):197-202. [Google Scholar]
Chrousos GP, Kaltsas G. Post-SARS sickness syndrome manifestations and endocrinopathy: how, why, and
so what? Clin Endocrinol (Oxf). 2005;63(4):363-5. [PubMed] [Google Scholar]
Touzot M, Beller CL, Touzot F, Louet AL, Piketty C. Dramatic interaction between levothyroxine and
lopinavir/ritonavir in a HIV-infected patient. AIDS. 2006;20(8):1210-2. [PubMed] [Google Scholar]
Wei L, Sun S, Zhang J, Hong Z, Xu Y, Ma Q, McNutt MA, Korteweg C, Gu J. Endocrine cells of the
adenohypophysis in severe acute respiratory syndrome (SARS). Biochem Cell Biol. 2010;88(4):723-30. [PubMed]
[Google Scholar]
Vignera SL, Cannarella R, Condorelli RA, Torre F, Aversa A, Calogero AE. Sex-specific SARS-CoV-2 mortality:
among hormone-modulated ACE2 expression, risk of venous thromboembolism and hypovitaminosis D. Int
J Mol Sci. 2020;21(8):2948. [PubMed] [Google Scholar]
Xu J, Qi L, Chi X, Yang J, Wei X, Gong E, Peh S, Gu J. Orchitis: a complication of severe acute respiratory
syndrome (SARS). Biol Reprod. 2006;74(2):410-16. [PubMed] [Google Scholar]
Sansone A, Mollaioli D, Ciocca G, Limoncin E, Colonnello E, Vena W, Jannini EA. Addressing male sexual and
reproductive health in wake of COVID-19 outbreak. J Endocrinological Invest. 2021;44(2):223-31. [Google
Scholar]
Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS. Thrombosis in hospitalized
patients With COVID-19 in a New York City health system. JAMA. 2020;324(8):799-801. [PubMed] [Google
Scholar]
Perini P, Nabulsi B, Massoni CB, Azzarone M, Freyrie A. Acute limb ischaemia in two young, non-atherosclerotic patients with COVID-19. Lancet. 2020;395(10236):1546. [PubMed] [Google Scholar]
Griffin DO, Jensen A, Khan M, Chin J, Chin K, Parnell R, Awwad C, Patel D. Arterial thromboembolic
complications in COVID-19 in low-risk patients despite prophylaxis. Br J Haematol. 2020;190(1):11-13. [Google
Scholar]
Hemasian H, Ansari B. First case of Covid-19 presented with cerebral venous thrombosis: a rare and dreaded
case. Rev Neurol (Paris). 2020 Jun;176(6):521-3. [PubMed] [Google Scholar]
Lodigiani C, Iapichino G, Carenzo L, Cecconi M, Ferrazzi P, Sebastian T, Kucher N, Studt JD, Sacco C, Bertuzzi A,
Sandri MT, Barco S, Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in
COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020;191:9-14. [PubMed]
[Google Scholar]
Zheng KI, Wang XB, Jin XH, Liu WY, Gao F, Chen YP, Zheng MH. A case series of recurrent viral RNA positivity in
recovered COVIDâ€19 Chinese patients. J Gen Intern Med. 2020;35(7):2205â€6. [PubMed] [Google Scholar]
Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, Tan KS, Wang DY, Yan Y. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status. Mil Med Res.
;7(1):11. [PubMed] [Google Scholar]
Carfì A, Bernabei R, Landi F, Gemelli against COVID-19 Post-Acute Care Study Group. Persistent symptoms in
patients after acute COVID-19. JAMA. 2020;324(6):603-5. [PubMed] [Google Scholar]
Abrams JY, Godfred-Cato SE, Oster ME, Chow EJ, Koumans EH, Bryant B, Leung JW, Belay ED. Multisystem
inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2: a systematic review. J Pediatr.
;226:45-54. [Google Scholar]
Machhi J, Herskovitz J, Senan AM, Dutta D, Nath B, Oleynikov MD, Blomberg WR, Meigs DD, Hasan M,
Patel M, Kline P, Chang RCC, Chang L, Gendelman HE, Kevadiya BD. The Natural History, Pathobiology,
and Clinical Manifestations of SARS-CoV-2 Infections. J Neuroimmune Pharmacol. 2020;15(3):359-86.
[PubMed] [Google Scholar]
Rawal G, Yadav S, Kumar R. Post-intensive Care Syndrome: an Overview. J Transl Int Med. 2017;5(2):90-
[PubMed] [Google Scholar]
Harvey MA, Davidson JE. Postintensive Care Syndrome Right Care, Right Now…and Later. Crit Care Med.
;44(2):381-5. [PubMed] [Google Scholar]
