Long-COVID: Current Understanding and Future Directions
DOI:
https://doi.org/10.55489/ijmr.1301202577Keywords:
Long-COVID, Post-acute sequelae, SARS-CoV-2, Persistent symptoms, Pathophysiology, Multidisciplinary managementAbstract
Long-COVID, or post-acute sequelae of SARS-CoV-2 infection, represents a significant global health challenge characterized by persistent symptoms lasting months after acute COVID-19. This narrative review synthesizes current understanding, exploring epidemiology, pathophysiology, clinical manifestations, diagnosis, management, and future directions. Prevalence estimates suggest 10-30% of survivors experience Long-COVID, with higher rates in women, middle-aged adults, and those with severe initial infections. Proposed mechanisms include viral persistence, immune dysregulation, endothelial dysfunction, and multi-organ damage, though causality remains uncertain due to observational study limitations. Common symptoms-fatigue, dyspnea, cognitive impairment, and joint pain-span systemic, respiratory, cardiovascular, and neurological domains, severely impacting quality of life. Diagnosis relies on clinical history and exclusion of differentials, lacking specific biomarkers. Management is symptom-focused, involving multidisciplinary rehabilitation, pacing, and emerging pharmacological trials, though evidence is limited by small sample sizes and biases. Future research prioritizes standardized definitions, longitudinal studies, and biomarker discovery to enable targeted therapies. Public health strategies must address inequities and integrate surveillance. Despite advances, gaps in understanding prognosis and treatment persist, necessitating increased funding and interdisciplinary collaboration to mitigate Long-COVID’s long-term burden and inform pandemic preparedness.
References
1. Centers for Disease Control and Prevention. Long COVID or post-COVID conditions. Available from: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
2. World Health Organization. Post COVID-19 condition (Long COVID). Available from: https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition
3. Callard F, Perego E. How and why patients made Long COVID. Soc Sci Med. 2021;268:113426. DOI: https://doi.org/10.1016/j.socscimed.2020.113426 PMid:33199035 PMCid:PMC7539940
4. Greenhalgh T, Knight M, A'Court C, Buxton M, Husain L. Management of post-acute COVID-19 in primary care. BMJ. 2020;370:m3026. DOI: https://doi.org/10.1136/bmj.m3026 PMid:32784198
5. National Academies of Sciences, Engineering, and Medicine. A Long COVID definition: A chronic, systemic disease state with profound consequences. Washington (DC): National Academies Press; 2024.
6. Han Q, Zheng B, Daines L, Sheikh A. Long-term sequelae of COVID-19: A systematic review and meta-analysis of one-year follow-up studies on post-COVID symptoms. Pathogens. 2022;11(2):269. DOI: https://doi.org/10.3390/pathogens11020269 PMid:35215212 PMCid:PMC8875269
7. Ford ND, Slaughter D, Edwards D, et al. Long COVID and significant activity limitation among adults, by age - United States, June 1-13, 2022, to June 7-19, 2023. MMWR Morb Mortal Wkly Rep. 2023;72(32):866-870. DOI: https://doi.org/10.15585/mmwr.mm7232a3 PMid:37561665 PMCid:PMC10415000
8. Fernández-de-Las-Peñas C, Notarte KI, Peligro PJ, et al. Long-COVID symptoms in individuals infected with different SARS-CoV-2 variants of concern: A systematic review and meta-analysis. Viruses. 2022;14(11):2454. DOI: https://doi.org/10.3390/v14112454 PMid:36366552 PMCid:PMC9699601
9. Wulf Hanson S, Abbafati C, Aerts JG, et al. A global systematic analysis of the occurrence, severity, and recovery pattern of long COVID in 2020 and 2021. medRxiv. 2022; DOI: https://doi.org/10.1101/2022.05.26.22275532
10. Behnood SA, Shafran R, Bennett SD, et al. Persistent symptoms following SARS-CoV-2 infection amongst children and young people: A meta-analysis of controlled and uncontrolled studies. J Infect. 2022;84(2):158-170. DOI: https://doi.org/10.1016/j.jinf.2021.11.011 PMid:34813820 PMCid:PMC8604800
11. Tsampasian V, Elghazaly H, Chattopadhyay R, et al. Risk factors associated with post-COVID-19 condition: A systematic review and meta-analysis. JAMA Intern Med. 2023;183(6):566-580. DOI: https://doi.org/10.1001/jamainternmed.2023.0750 PMid:36951832 PMCid:PMC10037203
12. Byambasuren O, Stehlik P, Clark J, et al. Effect of COVID-19 vaccination on long COVID: Systematic review. BMJ Med. 2023;2(1):e000385. DOI: https://doi.org/10.1136/bmjmed-2022-000385 PMid:36936268 PMCid:PMC9978692
13. Antonelli M, Pujol JC, Spector TD, Ourselin S, Steves CJ. Risk of long COVID associated with Delta versus Omicron variants of SARS-CoV-2. Lancet. 2022;399(10343):2263-2264. DOI: https://doi.org/10.1016/S0140-6736(22)00941-2 PMid:35717982
14. Perlis RH, Lunz Trujillo K, Safarpour A, et al. Community-based prevalence of long COVID in the United States: Analysis of a population-representative sample. medRxiv. 2023; doi:10.1101/2023.03.03.23286755
15. Adjaye-Gbewonyo D, Vahratian A, Perrine CG, Mullins J. Long COVID in adults: United States, 2022. NCHS Data Brief. 2023;(480):1-8. DOI: https://doi.org/10.15620/cdc:132417
16. Fernández-de-Las-Peñas C, Palacios-Ceña D, Gómez-Mayordomo V, et al. Defining post-COVID symptoms (post-acute COVID, long COVID, persistent post-COVID): An integrative classification. Int J Environ Res Public Health. 2021;18(5):2621. DOI: https://doi.org/10.3390/ijerph18052621 PMid:33807869 PMCid:PMC7967389
17. Proal AD, VanElzakker MB. Long COVID or post-acute sequelae of COVID-19 (PASC): An overview of biological factors that may contribute to persistent symptoms. Front Microbiol. 2021;12:698169. DOI: https://doi.org/10.3389/fmicb.2021.698169 PMid:34248921 PMCid:PMC8260991
18. Castanares-Zapatero D, Chalon P, Kohn L, et al. Pathophysiology and mechanism of long COVID: A comprehensive review. Ann Med. 2022;54(1):1473-1487. DOI: https://doi.org/10.1080/07853890.2022.2076901 PMid:35594336 PMCid:PMC9132392
19. Chen C, Haupert SR, Zimmermann L, et al. Global prevalence of post-coronavirus disease 2019 (COVID-19) condition or long COVID: A meta-analysis and systematic review. J Infect Dis. 2022;226(9):1593-1607. DOI: https://doi.org/10.1093/infdis/jiac136 PMid:35429399 PMCid:PMC9047189
20. Swank Z, Senussi Y, Manickas-Hill Z, et al. Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae. Clin Infect Dis. 2023;76(3):e487-e490. DOI: https://doi.org/10.1093/cid/ciac722 PMid:36052466 PMCid:PMC10169416
21. Phetsouphanh C, Darley DR, Wilson DB, et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol. 2022;23(2):210-216. DOI: https://doi.org/10.1038/s41590-021-01113-x PMid:35027728
22. Monje M, Iwasaki A. The neurobiology of long COVID. Neuron. 2022;110(21):3484-3496. DOI: https://doi.org/10.1016/j.neuron.2022.10.006 PMid:36288726 PMCid:PMC9537254
23. Pretorius E, Vlok M, Venter C, et al. Persistent clotting protein pathology in long COVID/post-acute sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc Diabetol. 2021;20(1):172. DOI: https://doi.org/10.1186/s12933-021-01359-7 PMid:34425843 PMCid:PMC8381139
24. Choutka J, Jansari V, Hornig M, Iwasaki A. Unexplained post-acute infection syndromes. Nat Med. 2022;28(5):911-923. DOI: https://doi.org/10.1038/s41591-022-01810-6 PMid:35585196
25. Pairo-Castineira E, Clohisey S, Klaric L, et al. Genetic mechanisms of critical illness in COVID-19. Nature. 2021;591(7848):92-98. DOI: https://doi.org/10.1038/s41586-020-03065-y PMid:33307546
26. Lopez-Leon S, Wegman-Ostrosky T, Perelman C, et al. More than 50 long-term effects of COVID-19: A systematic review and meta-analysis. Sci Rep. 2021;11(1):16144. DOI: https://doi.org/10.1038/s41598-021-95565-8 PMid:34373540 PMCid:PMC8352980
27. Komaroff AL, Bateman L. Will COVID-19 lead to myalgic encephalomyelitis/chronic fatigue syndrome? Front Med (Lausanne). 2021;7:606824. DOI: https://doi.org/10.3389/fmed.2020.606824 PMid:33537329 PMCid:PMC7848220
28. Torres-Castro R, Vasconcello-Castillo L, Alsina-Restoy X, et al. Respiratory function in patients post-infection by COVID-19: A systematic review and meta-analysis. Pulmonology. 2021;27(4):328-337. DOI: https://doi.org/10.1016/j.pulmoe.2020.10.013 PMid:33262076 PMCid:PMC7687368
29. Raman B, Bluemke DA, Lüscher TF, Neubauer S. Long COVID: Post-acute sequelae of COVID-19 with a cardiovascular focus. Eur Heart J. 2022;43(11):1157-1172. DOI: https://doi.org/10.1093/eurheartj/ehac031 PMid:35176758 PMCid:PMC8903393
30. Douaud G, Lee S, Alfaro-Almagro F, et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. 2022;604(7907):697-707. DOI: https://doi.org/10.1038/s41586-022-04569-5 PMid:35255491 PMCid:PMC9046077
31. 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):603-605. DOI: https://doi.org/10.1001/jama.2020.12603 PMid:32644129 PMCid:PMC7349096
32. Kenny G, McCann K, O'Brien C, et al. Identification of distinct long COVID clinical phenotypes through cluster analysis of self-reported symptoms. Open Forum Infect Dis. 2022;9(4):ofac060. DOI: https://doi.org/10.1093/ofid/ofac060 PMid:35265728 PMCid:PMC8900926
33. Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019. DOI: https://doi.org/10.1016/j.eclinm.2021.101019 PMid:34308300 PMCid:PMC8280690
34. Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV; WHO Clinical Case Definition Working Group on Post-COVID-19 Condition. A clinical case definition of post-COVID-19 condition by a Delphi consensus. Lancet Infect Dis. 2022;22(4):e102-e107. DOI: https://doi.org/10.1016/S1473-3099(21)00703-9 PMid:34951953
35. Centers for Disease Control and Prevention. Evaluating and caring for patients with post-COVID conditions: Interim guidance. Available from: https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-index.html
36. Klok FA, Boon GJAM, Barco S, et al. The Post-COVID-19 Functional Status scale: A tool to measure functional status over time after COVID-19. Eur Respir J. 2020;56(1):2001494. DOI: https://doi.org/10.1183/13993003.01494-2020 PMid:32398306 PMCid:PMC7236834
37. Crook H, Raza S, Nowell J, Young M, Edison P. Long COVID-mechanisms, risk factors, and management. BMJ. 2021;374:n1648. DOI: https://doi.org/10.1136/bmj.n1648 PMid:34312178
38. Yelin D, Moschopoulos CD, Margalit I, et al. ESCMID rapid guidelines for assessment and management of long COVID. Clin Microbiol Infect. 2022;28(7):955-972. DOI: https://doi.org/10.1016/j.cmi.2022.02.018 PMid:35182760 PMCid:PMC8849856
39. O'Mahoney LL, Routen A, Gillies C, et al. The prevalence and long-term health effects of long COVID among hospitalised and non-hospitalised populations: A systematic review and meta-analysis. EClinicalMedicine. 2023;55:101762. DOI: https://doi.org/10.1016/j.eclinm.2022.101762 PMid:36474804 PMCid:PMC9714474
40. McCarthy MW. Paxlovid as a potential treatment for long COVID. Expert Rev Anti Infect Ther. 2023;21(8):781-785. DOI: https://doi.org/10.1080/14656566.2023.2262387 PMid:37731377
41. Charfeddine S, Ibn Hadj Amor H, Jdidi J, et al. Long COVID 19 syndrome: Is it related to microcirculation and endothelial dysfunction? Insights from TUN-EndCOV study. Front Cardiovasc Med. 2021;8:745788. DOI: https://doi.org/10.3389/fcvm.2021.745758 PMid:34917659 PMCid:PMC8670225
42. Nurek M, Rayner C, Freyer A, et al. Recommendations for the recognition, diagnosis, and management of long COVID: A Delphi study. Br J Gen Pract. 2021;71(712):e815-e825. DOI: https://doi.org/10.3399/BJGP.2021.0265 PMid:34607799 PMCid:PMC8510689
43. Writing Committee for the REMAP-CAP Investigators. Effect of antiplatelet therapy on survival and organ support-free days in critically ill patients with COVID-19: A randomized clinical trial. JAMA. 2022;327(13):1247-1259. DOI: https://doi.org/10.1001/jama.2022.23257 PMid:36525245 PMCid:PMC9857594
44. Al-Aly Z, Topol EJ. Solving the puzzle of long COVID. Science. 2024;383(6685):830-832. DOI: https://doi.org/10.1126/science.adl0867 PMid:38386747
45. Ledford H. Long COVID treatments: Where are we at? Nature. 2023;611(7935):S18-S20.
46. Michelen M, Manoharan L, Elkheir N, et al. Characterising long COVID: A living systematic review. BMJ Glob Health. 2021;6(9):e005427. DOI: https://doi.org/10.1136/bmjgh-2021-005427 PMid:34580069 PMCid:PMC8478580
47. Topol EJ. AI in medicine: Where are we now and where are we going? Cell. 2023;186(12):2487-2489.
48. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-733. DOI: https://doi.org/10.1056/NEJMoa2001017 PMid:31978945 PMCid:PMC7092803
49. A clinical case definition of post COVID-19 condition by a Delphi consensus, 6 October 2021. World Health Organization; 2021. Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1
50. Paul BD, Lemle MD, Komaroff AL, Snyder SH. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2021;118(34):e2024358118. DOI: https://doi.org/10.1073/pnas.2024358118 PMid:34400495 PMCid:PMC8403932
51. Fernández-de-Las-Peñas C, Ryan-Murua P, de-la-Llave-Rincón AI, et al. Serological biomarkers at hospital admission and hospitalization treatments are not related to long-COVID-19 syndrome in patients with SARS-CoV-2 infection. J Med Virol. 2023;95(11):e29211. DOI: https://doi.org/10.1002/jmv.29211 PMid:37975336
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