Long COVID across SARS-CoV-2 variants: Clinical features, pathogenesis, and future directions

Abstract

Long coronavirus disease (COVID) is characterized by persistent symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and has emerged as a significant health concern. As SARS-CoV-2 evolved from the wild-type strain to the Alpha, Beta, Delta, and Omicron variants, there may be a variant-specific influence on long COVID akin to the acute disease. This review aims to summarize our current knowledge of variant-specific influences in long COVID incidence, symptom profile as well as mechanisms of pathogenesis. We highlight that long COVID incidence may be lower with the Omicron variants. The symptom profile of long COVID may also show some dependence on the different variants, with a reduction in cardiopulmonary symptoms with more recent SARS-CoV-2 variants. This heterogeneity of long COVID may also be related to the variant-specific differences in affecting the immune system, viral persistence, and autoimmunity. However, emerging data also suggest that vaccinations may play a big role in shaping the presentation of long COVID. We also highlight ongoing work on long COVID incidence and symptom profiles in populations infected only by the Omicron variants. This will be beneficial toward more useful disease definitions and the development of effective diagnostic and therapeutic strategies.

Keywords

chronic fatigue syndromes / long-haul COVID / PASC / postacute COVID-19 syndrome

References

[1] ZhouP, YangXL, WangXG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-273.

[2] WuF, ZhaoS, YuB, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020;579(7798):265-269.

[3] ZhuN, ZhangD, WangW, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-733.

[4] DongE, DuH, GardnerL. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020;20(5):533-534.

[5] NalbandianA, SehgalK, GuptaA, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601-615.

[6] LiJ, ZhouY, MaJ, et al. The long-term health outcomes, pathophysiological mechanisms and multidisciplinary management of long COVID. Signal Transduct Target Ther. 2023;8:416.

[7] ChouR, HermanE, AhmedA, et al. Long COVID definitions and models of care . Published online May 21, 2024.

[8] ElyEW, BrownLM, FinebergHV. Long covid defined. N Engl J Med. 2024;391:1746-1753.

[9] Al-AlyZ, DavisH, McCorkellL, et al. Long COVID science, research and policy. Nature Med. 2024;30(8):2148-2164.

[10] SudreCH, MurrayB, VarsavskyT, et al. Attributes and predictors of long COVID. Nat Med. 2021;27(4):626-631.

[11] AoD, LanT, HeX, et al. SARS-CoV-2 Omicron variant: immune escape and vaccine development. MedComm. 2022;3(1):e126.

[12] KhareS, GurryC, FreitasL, et al. GISAID’s role in pandemic response. China CDC Weekly. 2021;3(49):1049-1051.

[13] PayneS. Family coronaviridae. Viruses. 2017:149-158.

[14] SnijderEJ, Decroly E, ZiebuhrJ. The nonstructural proteins directing coronavirus RNA synthesis and processing. Adv Virus Res. 2016;96:59-126.

[15] MastersPS. The molecular biology of coronaviruses. Adv Virus Res. 2006;66:193-292.

[16] HulswitRJG, de Haan CAM, BoschBJ. Coronavirus spike protein and tropism changes. Adv Virus Res. 2016;96:29-57.

[17] BoschBJ, van der Zee R, de HaanCAM, RottierPJM. The coronavirus spike protein is a class I virus fusion protein: structural and functional characterization of the fusion core complex. J Virol. 2003;77(16):8801-8811.

[18] LiF. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol. 2016;3(1):237-261.

[19] DucheneS, Featherstone L, Haritopoulou-SinanidouM, RambautA, Lemey P, BaeleG. Temporal signal and the phylodynamic threshold of SARS-CoV-2. Virus Evol. 2020;6(2):veaa061.

[20] CarabelliAM, Peacock TP, ThorneLG, et al. SARS-CoV-2 variant biology: immune escape, transmission and fitness. Nat Rev Microbiol. 2023;21(3):162-177.

[21] Muñoz-FontelaC, Dowling WE, FunnellSGP, et al. Animal models for COVID-19. Nature. 2020;586(7830):509-515.

[22] FanC, WuY, RuiX, et al. Animal models for COVID-19: advances, gaps and perspectives. Signal Transduct Target Ther. 2022;7(1):220.

[23] EhaidebSN, Abdullah ML, AbuyassinB, BouchamaA. Evidence of a wide gap between COVID-19 in humans and animal models: a systematic review. Crit Care. 2020;24(1):594.

[24] AndreM, LauLS, PokharelMD, et al. From Alpha to Omicron: how different variants of concern of the SARS-Coronavirus-2 impacted the world. Biology. 2023;12(9):1267.

[25] DuongD. Alpha, Beta, Delta, Gamma: what’s important to know about SARS-CoV-2 variants of concern? Can Med Assoc J. 2021;193(27):E1059-E1060.

[26] LoconsoleD, Centrone F, MorcavalloC, et al. Changing features of COVID-19: characteristics of infections with the SARS-CoV-2 delta (B.1.617.2) and alpha (B.1.1.7) variants in Southern Italy. Vaccines. 2021;9(11):1354.

[27] DaviesNG, JarvisCI, EdmundsWJ, Jewell NP, Diaz-OrdazK, KeoghRH. Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7. Nature. 2021;593(7858):270-274.

[28] LinL, LiuY, TangX, He D. The disease severity and clinical outcomes of the SARS-CoV-2 variants of concern. Front Public Health. 2021;9:775224.

[29] MengB, KempSA, PapaG, et al. Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7. Cell Rep. 2021;35(13):109292.

[30] HuangY, YangC, XuX, XuW, LiuS. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol Sin. 2020;41(9):1141-1149.

[31] YurkovetskiyL, WangX, PascalKE, et al. Structural and functional analysis of the D614G SARS-CoV-2 spike protein variant. Cell. 2020;183(3):739-751.e8.

[32] McCarthyKR, Rennick LJ, NambulliS, et al. Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape. Science. 2021;371(6534):1139-1142.

[33] JassatW, Abdool Karim SS, MudaraC, et al. Clinical severity of COVID-19 in patients admitted to hospital during the omicron wave in South Africa: a retrospective observational study. Lancet Glob Health. 2022;10(7):e961-e969.

[34] FismanDN, TuiteAR. Evaluation of the relative virulence of novel SARS-CoV-2 variants: a retrospective cohort study in Ontario, Canada. Can Med Assoc J. 2021;193(42):E1619-E1625.

[35] TegallyH, Wilkinson E, GiovanettiM, et al. Detection of a SARS-CoV-2 variant of concern in South Africa. Nature. 2021;592(7854):438-443.

[36] BhattacharyaM, Chatterjee S, SharmaAR, AgoramoorthyG, Chakraborty C. D614G mutation and SARS-CoV-2: impact on S-protein structure, function, infectivity, and immunity. Appl Microbiol Biotechnol. 2021;105(24):9035-9045.

[37] PlanteJA, LiuY, LiuJ, et al. Spike mutation D614G alters SARS-CoV-2 fitness. Nature. 2021;592(7852):116-121.

[38] SinhaS, TamB, WangSM. RBD double mutations of SARS-CoV-2 strains increase transmissibility through enhanced interaction between RBD and ACE2 receptor. Viruses. 2021;14(1):1.

[39] WibmerCK, AyresF, HermanusT, et al. SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. Nat Med. 2021;27(4):622-625.

[40] JohnsonBA, XieX, BaileyAL, et al. Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis. Nature. 2021;591(7849):293-299.

[41] PlanasD, VeyerD, BaidaliukA, et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature. 2021;596(7871):276-280.

[42] ChoiJY, SmithDM. SARS-CoV-2 variants of concern. Yonsei Med J. 2021;62(11):961.

[43] TchesnokovaV, Kulasekara H, LarsonL, et al. Acquisition of the L452R mutation in the ACE2-binding interface of spike protein triggers recent massive expansion of SARS-CoV-2. J Clin Microbiol. 2021;59(11):e0092121.

[44] AugustoG, MohsenMO, ZinkhanS, Liu X, VogelM, BachmannMF. In vitro data suggest that Indian delta variant B.1.617 of SARS-CoV-2 escapes neutralization by both receptor affinity and immune evasion. Allergy. 2022;77(1):111-117.

[45] ArabiM, Al-Najjar Y, MhaimeedN, et al. Severity of the Omicron SARS-CoV-2 variant compared with the previous lineages: a systematic review. J Cell Mol Med. 2023;27(11):1443-1464.

[46] Lopez BernalJ, Andrews N, GowerC, et al. Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) variant. N Engl J Med. 2021;385(7):585-594.

[47] SuzukiR, Yamasoba D, KimuraI, et al. Attenuated fusogenicity and pathogenicity of SARS-CoV-2 Omicron variant. Nature. 2022;603(7902):700-705.

[48] RoemerC, Sheward DJ, HisnerR, et al. SARS-CoV-2 evolution in the Omicron era. Nat Microbiol. 2023;8(11):1952-1959.

[49] HuFH, JiaYJ, ZhaoDY, et al. Clinical outcomes of the severe acute respiratory syndrome coronavirus 2 Omicron and Delta variant: systematic review and meta-analysis of 33 studies covering 6 037 144 coronavirus disease 2019–positive patients. Clin Microbiol Infect. 2023;29(7):835-844.

[50] ZhouY, ZhiH, TengY. The outbreak of SARS-CoV-2 Omicron lineages, immune escape, and vaccine effectivity. J Med Virol. 2023;95(1):e28138.

[51] DesinguPA, Nagarajan K, DhamaK. Emergence of omicron third lineage BA.3 and its importance. J Med Virol. 2022;94(5):1808-1810.

[52] ShahM, WooHG. Omicron: a heavily mutated SARS-CoV-2 variant exhibits stronger binding to ACE2 and potently escapes approved COVID-19 therapeutic antibodies. Front Immunol. 2022;12:830527.

[53] PlanasD, Saunders N, MaesP, et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature. 2022;602(7898):671-675.

[54] HoffmannM, Krüger N, SchulzS, et al. The Omicron variant is highly resistant against antibody-mediated neutralization: implications for control of the COVID-19 pandemic. Cell. 2022;185(3):447-456.e11.

[55] TegallyH, MoirM, EverattJ, et al. Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa. Nat Med. 2022;28(9):1785-1790.

[56] WangQ, GuoY, IketaniS, et al. Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5. Nature. 2022;608(7923):603-608.

[57] MenegaleF, ManicaM, ZardiniA, et al. Evaluation of waning of SARS-CoV-2 vaccine-induced immunity: a systematic review and meta-analysis. JAMA Network Open. 2023;6(5):e2310650.

[58] WangQ, Iketani S, LiZ, et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell. 2023;186(2):279-286.e8.

[59] CaoY, SongW, WangL, et al. Characterization of the enhanced infectivity and antibody evasion of Omicron BA.2.75. Cell Host Microbe. 2022;30(11):1527-1539.e5.

[60] ChakrabortyC, Bhattacharya M, ChopraH, IslamMA, Saikumar G, DhamaK. The SARS-CoV-2 Omicron recombinant subvariants XBB, XBB.1, and XBB.1.5 are expanding rapidly with unique mutations, antibody evasion, and immune escape properties—an alarming global threat of a surge in COVID-19 cases again? Int J Surg. 2023;109(4):1041-1043.

[61] KurhadeC, ZouJ, XiaH, et al. Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster. Nat Med. 2023;29(2):344-347.

[62] UriuK, ItoJ, KosugiY, et al. Transmissibility, infectivity, and immune evasion of the SARS-CoV-2 BA.2.86 variant. Lancet Infect Dis. 2023;23(11):e460-e461.

[63] KakuY, Okumura K, Padilla-BlancoM, et al. Virological characteristics of the SARS-CoV-2 JN.1 variant. Lancet Infect Dis. 2024;24(2):e82.

[64] YangS, YuY, XuY, et al. Fast evolution of SARS-CoV-2 BA.2.86 to JN.1 under heavy immune pressure. Lancet Infect Dis. 2024;24(2):e70-e72.

[65] KakuY, UriuK, KosugiY, et al. Virological characteristics of the SARS-CoV-2 KP.2 variant. Lancet Infect Dis. 2024;24(7):e416.

[66] Fernández-de-las-PeñasC, NotarteKI, Peligro PJ, et al. Long-COVID symptoms in individuals infected with different SARS-CoV-2 variants of concern: a systematic review of the literature. Viruses. 2022;14(12):2629.

[67] DuM, MaY, DengJ, Liu M, LiuJ. Comparison of long COVID-19 caused by different SARS-CoV-2 strains: a systematic review and meta-analysis. Int J Environ Res Public Health. 2022;19(23):16010.

[68] Hernández-AceitunoA, García-HernándezA, Larumbe-ZabalaE. COVID-19 long-term sequelae: omicron versus Alpha and Delta variants. Infectious Diseases Now. 2023;53(5):104688.

[69] AntonelliM, PujolJC, SpectorTD, Ourselin S, StevesCJ. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. Lancet. 2022;399(10343):2263-2264.

[70] SaigalA, Nagoda Niklewicz C, NaiduSB, et al. Cross-sectional study evaluating the impact of SARS-CoV-2 variants on long COVID outcomes in UK hospital survivors. BMJ Open Respir Res. 2023;10(1):e001667.

[71] SpinicciM, Graziani L, TilliM, et al. Infection with SARS-CoV-2 variants is associated with different long COVID phenotypes. Viruses. 2022;14(11):2367.

[72] XieY, ChoiT, Al-AlyZ. Postacute sequelae of SARS-CoV-2 infection in the pre-Delta, Delta, and Omicron eras. N Engl J Med. 2024;391:515-525.

[73] de BruijnS, van Hoek AJ, MutubukiEN, et al. Lower prevalence of post-Covid-19 condition following Omicron SARS-CoV-2 infection. Heliyon. 2024;10(7):e28941.

[74] BabickiM, Kołat D, Kałuzińska-Kołat Ż, et al. The course of COVID-19 and long COVID: identifying risk factors among patients suffering from the disease before and during the Omicron-dominant period. Pathogens. 2024;13(3):267.

[75] Thi KhanhHN, Cornelissen L, Castanares-ZapateroD, et al. Association between SARS-CoV-2 variants and post-COVID-19 condition: findings from a longitudinal cohort study in the Belgian adult population. BMC Infect Dis. 2023;23(1):774.

[76] WillanJ, Agarwal G, BienzN. Mortality and burden of post-COVID-19 syndrome have reduced with time across SARS-CoV-2 variants in haematology patients. Br J Haematol. 2023;201(4):640-644.

[77] BuonsensoD, Morello R, MarianiF, et al. Risk of long Covid in children infected with Omicron or pre-Omicron SARS-CoV-2 variants. Acta Paediatr (Stockholm). 2023;112(6):1284-1286.

[78] LokanuwatsatienT, Satdhabudha A, TangsathapornpongA, et al. Prevalence and associating factors of long COVID in pediatric patients during the Delta and the Omicron variants. Front Pediatr. 2023;11:1127582.

[79] KahlertCR, StrahmC, GüsewellS, et al. Post-acute sequelae after severe acute respiratory syndrome coronavirus 2 infection by viral variant and vaccination status: a multicenter cross-sectional study. Clin Infect Dis. 2023;77(2):194-202.

[80] Bello-ChavollaOY, Fermín-Martínez CA, Ramírez-García D, et al. Prevalence and determinants of post-acute sequelae after SARS-CoV-2 infection (long COVID) among adults in Mexico during 2022: a retrospective analysis of nationally representative data. Lancet Reg Health Am. 2024;30:100688.

[81] DiexerS, KleeB, GottschickC, et al. Association between virus variants, vaccination, previous infections, and post COVID-19 risk. Int J Infect Dis. 2023:136:14-21.

[82] PazukhinaE, Rumyantsev M, BaimukhambetovaD, et al. Event rates and incidence of post-COVID-19 condition in hospitalised SARS-CoV-2 positive children and young people and controls across different pandemic waves: exposure-stratified prospective cohort study in Moscow (StopCOVID). BMC Med. 2024;22(1):48.

[83] ErtesvågNU, Iversen A, BlombergB, et al. Post COVID-19 condition after delta infection and omicron reinfection in children and adolescents. EBioMedicine. 2023;92:104599.

[84] MichelenM, Manoharan L, ElkheirN, et al. Characterising long COVID: a living systematic review. BMJ Glob Health. 2021;6(9):e005427.

[85] MichelenM, Manoharan L, ElkheirN, et al. Characterising long COVID: a living systematic review. BMJ Glob Health. 2021;6(9):e005427.

[86] LuoJ, ZhangJ, TangHT, et al. Prevalence and risk factors of long COVID 6-12 months after infection with the Omicron variant among nonhospitalized patients in Hong Kong. J Med Virol. 2023;95(6):e28862.

[87] PenetraSLS, da Silva MFB, ResendeP, et al. Post-acute COVID-19 syndrome after reinfection and vaccine breakthrough by the SARS-CoV-2 Gamma variant in Brazil. Int J Infect Dis. 2022;114:58-61.

[88] O’MahoneyLL, Routen A, GilliesC, 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.

[89] GenecandL, Altarelli M, BinkovaA, et al. Dysfunctional breathing symptoms, functional impact and quality of life in patients with long COVID-19: a prospective case series. BMJ Open Respir Res. 2023;10(1):e001770.

[90] CebanF, LingS, LuiLMW, et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022;101:93-135.

[91] NasserieT, HittleM, GoodmanSN. Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: a systematic review. JAMA Netw Open. 2021;4(5):e2111417.

[92] HoweS, SzanyiJ, BlakelyT. The health impact of long COVID during the 2021-2022 Omicron wave in Australia: a quantitative burden of disease study. Int J Epidemiol. 2023;52(3):677-689.

[93] CaiM, XieY, TopolEJ, Al-Aly Z. Three-year outcomes of post-acute sequelae of COVID-19. Nat Med. 2024;30(6):1564-1573.

[94] CanasLS, Molteni E, DengJ, et al. Profiling post-COVID-19 condition across different variants of SARS-CoV-2: a prospective longitudinal study in unvaccinated wild-type, unvaccinated alpha-variant. and vaccinated delta-variant populations. Lancet Digit Health. 2023;5(7):e421-e434.

[95] AloèT, Novelli F, PuppoG, et al. Prevalence of long COVID symptoms related to SARS-CoV-2 strains. Life. 2023;13(7):1558.

[96] LiaoX, GuanY, LiaoQ, et al. Long-term sequelae of different COVID-19 variants: the original strain versus the Omicron variant. Glob Health Med. 2022;4(6):322-326.

[97] Fernández-De-las-peñasC, Cancela-CillerueloI, Rodríguez-Jiménez J, et al. Associated-onset symptoms and post-COVID-19 symptoms in hospitalized COVID-19 survivors infected with Wuhan, Alpha or Delta SARS-CoV-2 variant. Pathogens. 2022;11(7):725.

[98] PerczeAR, NagyA, PolivkaL, et al. Fatigue, sleepiness and sleep quality are SARS-CoV-2 variant independent in patients with long COVID symptoms. Inflammopharmacology. 2023;31:2819-2825.

[99] AgergaardJ, GunstJD, Schiøttz-ChristensenB, ØstergaardL, Wejse C. Long-term prognosis at 1.5 years after infection with wild-type strain of SARS-CoV-2 and Alpha, Delta, as well as Omicron variants. Int J Infect Dis. 2023;137:126-133.

[100] CaiJ, LinK, ZhangH, et al. A one-year follow-up study of systematic impact of long COVID symptoms among patients post SARS-CoV-2 omicron variants infection in Shanghai, China. Emerg Microbes Infect. 2023;12(2):2220578.

[101] Pinto PereiraSM, Nugawela MD, McOwatK, et al. Symptom profiles of children and young people 12 months after SARS-CoV-2 testing: a national matched cohort study (The CLoCk Study). Children. 2023;10(7):1227.

[102] Pinto PereiraSM, MensahA, NugawelaMD, et al. Long COVID in children and young after infection or reinfection with the omicron variant: a prospective observational study. J Pediatr. 2023;259:113463.

[103] MorelloR, Mariani F, MastrantoniL, et al. Risk factors for post-COVID-19 condition (Long Covid) in children: a prospective cohort study. EClinicalMedicine. 2023;59:101961.

[104] Yildirim ArslanS, Avcu G, Sahbudak BalZ, ArslanA, Ozkinay FF, KurugolZ. Evaluation of post-COVID symptoms of the SARS-CoV-2 Delta and Omicron variants in children: a prospective study. Eur J Pediatr. 2023;182:4565-4571.

[105] DavisHE, McCorkell L, VogelJM, TopolEJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133-146.

[106] MonjeM, Iwasaki A. The neurobiology of long COVID. Neuron. 2022;110(21):3484-3496.

[107] WuX, XiangM, JingH, Wang C, NovakovicVA, ShiJ. Damage to endothelial barriers and its contribution to long COVID. Angiogenesis. 2024;27(1):5-22.

[108] IsaA, Kasprowicz V, NorbeckO, et al. Prolonged activation of virus-specific CD8 + T cells after acute B19 infection. PLoS Med. 2005;2(12):e343.

[109] ZhaoM, ChenJ, TanS, et al. Prolonged evolution of virus-specific memory T cell immunity after severe avian influenza A (H7N9) virus infection. J Virol. 2018;92(17):e01024-18.

[110] KleinJ, WoodJ, JaycoxJR, et al. Distinguishing features of long COVID identified through immune profiling. Nature. 2023;623(7985):139-148.

[111] FilesJK, Boppana S, PerezMD, et al. Sustained cellular immune dysregulation in individuals recovering from SARS-CoV-2 infection. J Clin Invest. 2021;131(1):e140491.

[112] TaeschlerP, AdamoS, DengY, et al. T-cell recovery and evidence of persistent immune activation 12 months after severe COVID-19. Allergy. 2022;77(8):2468-2481.

[113] LeeLH, LawJWF, TanLTH, Letchumanan V, LimHX. IDDF2024-ABS-0299 Gut microbiota changes in relation to long-COVID-19 syndrome. Gut. 2024;73(suppl 2):A192.

[114] YinYS, Minacapelli CD, ParmarV, et al. Alterations of the fecal microbiota in relation to acute COVID-19 infection and recovery. Mol Biomed. 2022;3(1):36.

[115] WongAC, Devason AS, UmanaIC, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023:186(22):4851-4867.e20.

[116] SarkarS, Monteiro O. Understanding long COVID—The role of serotonin in cognitive impairment. MedComm—Future Medicine. 2024;3(2):e80.

[117] PhetsouphanhC, DarleyDR, WilsonDB, et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol. 2022;23(2):210-216.

[118] BastardP, Gervais A, Le VoyerT, et al. Autoantibodies neutralizing type I IFNs are present in ∼ 4% of uninfected individuals over 70 years old and account for ∼ 20% of COVID-19 deaths. Sci Immunol. 2021;6(62):eabl4340.

[119] SmithN, Possémé C, BondetV, et al. Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity. Nat Commun. 2022;13(1):1-14.

[120] PelusoMJ, LuS, TangAF, et al. Markers of immune activation and inflammation in individuals with postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection. J Infect Dis. 2021;224(11):1839-1848.

[121] LaineL, Skön M, VäisänenE, JulkunenI, Österlund P. SARS-CoV-2 variants Alpha, Beta, Delta and Omicron show a slower host cell interferon response compared to an early pandemic variant. Front Immunol. 2022;13:1016108.

[122] GaneshR, YadavS, HurtRT, et al. Pro inflammatory cytokines profiles of patients with long COVID differ between variant epochs. J Prim Care Community Health. 2024;15:21501319241254751.

[123] GuoK, Barrett BS, MorrisonJH, et al. Interferon resistance of emerging SARS-CoV-2 variants. Proc Natl Acad Sci U S A. 2022;119(32):e2203760119.

[124] ListaMJ, Winstone H, WilsonHD, et al. The P681H mutation in the spike glycoprotein of the Alpha variant of SARS-CoV-2 escapes IFITM restriction and is necessary for type I interferon resistance. J Virol. 2022;96(23):e0125022.

[125] TarkeA, SidneyJ, KiddCK, et al. Comprehensive analysis of T cell immunodominance and immunoprevalence of SARS-CoV-2 epitopes in COVID-19 cases. Cell Rep Med. 2021;2(2):100204.

[126] WajnbergA, AmanatF, FirpoA, et al. Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science (New York, N.Y.). 2020;370(6521):1227-1230.

[127] HuangAT, Garcia-Carreras B, HitchingsMDT, et al. A systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity. Nat Commun. 2020;11(1):1-16.

[128] HallVJ, Foulkes S, CharlettA, et al. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN). Lancet. 2021;397(10283):1459-1469.

[129] KhouryDS, CromerD, ReynaldiA, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021;27(7):1205-1211.

[130] BuckAM, Deitchman AN, TakahashiS, et al. The breadth of the neutralizing antibody response to original SARS-CoV-2 infection is linked to the presence of Long COVID symptoms. J Med Virol. 2023;95(11):e29216.

[131] AugustinM, Schommers P, StecherM, et al. Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study. Lancet Reg Health Eur. 2021;6:100122.

[132] García-AbellánJ, PadillaS, Fernández-González M, et al. Antibody response to SARS-CoV-2 is associated with long-term clinical outcome in patients with COVID-19: a longitudinal study. J Clin Immunol. 2021;41(7):1490-1501.

[133] JansenEB, Ostadgavahi AT, HewinsB, et al. PASC (Post Acute Sequelae of COVID-19) is associated with decreased neutralizing antibody titers in both biological sexes and increased ANG-2 and GM-CSF in females. Sci Rep. 2024;14(1):9854.

[134] Al-AlyZ, BoweB, XieY. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med. 2022;28(7):1461-1467.

[135] GriffinDE. Why does viral RNA sometimes persist after recovery from acute infections? PLoS Biol. 2022;20(6):e3001687.

[136] BrodinP, CasariG, TownsendL, et al. Studying severe long COVID to understand post-infectious disorders beyond COVID-19. Nat Med. 2022;28(5):879-882.

[137] GaeblerC, WangZ, LorenziJCC, et al. Evolution of antibody immunity to SARS-CoV-2. Nature. 2021;591(7851):639-644.

[138] NatarajanA, ZlitniS, BrooksEF, et al. Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection. Med. 2022;3(6):371-387.e9.

[139] SwankZ, Senussi Y, Manickas-HillZ, et al. Persistent circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae. Clin Infect Dis. 2023;76(3):e487-e490.

[140] LiR, YuanX, ZhangL, et al. 3D printing of microneedle arrays for hair regeneration in a controllable region. Mol Biomed. 2023;4(1):1-4.

[141] PattersonBK, Francisco EB, YogendraR, et al. Persistence of SARS CoV-2 S1 protein in CD16+ monocytes in post-acute sequelae of COVID-19 (PASC) up to 15 months post-infection. Front Immunol. 2022;12:746021.

[142] Maffia-BizzozeroS, Cevallos C, LenicovFR, et al. Viable SARS-CoV-2 Omicron sub-variants isolated from autopsy tissues. Front Microbiol. 2023;14:1192832.

[143] CeulemansLJ, KhanM, YooSJ, et al. Persistence of SARS-CoV-2 RNA in lung tissue after mild COVID-19. Lancet Respir Med. 2021;9(8):e78-e79.

[144] CheungCCL, GohD, LimX, et al. Residual SARS-CoV-2 viral antigens detected in GI and hepatic tissues from five recovered patients with COVID-19. Gut. 2022;71(1):226-229.

[145] Menuchin-LasowskiY, Schreiber A, LecandaA, et al. SARS-CoV-2 infects and replicates in photoreceptor and retinal ganglion cells of human retinal organoids. Stem Cell Reports. 2022;17(4):789-803.

[146] TejerinaF, Catalan P, Rodriguez-GrandeC, et al. Post-COVID-19 syndrome. SARS-CoV-2 RNA detection in plasma, stool, and urine in patients with persistent symptoms after COVID-19. BMC Infect Dis. 2022;22(1):211.

[147] CalvetGA, KaraE, GonsalvesL, et al. Viral shedding of SARS-CoV-2 in body fluids associated with sexual activity: a systematic review and meta-analysis. BMJ Open. 2024;14(2):e073084.

[148] ZuoW, HeD, LiangC, et al. The persistence of SARS-CoV-2 in tissues and its association with long COVID symptoms: a cross-sectional cohort study in China. Lancet Infect Dis. 2024;24(8):845-855.

[149] KennyG, Townsend L, SavinelliS, MallonPWG. Long COVID: clinical characteristics, proposed pathogenesis and potential therapeutic targets. Front Mol Biosci. 2023;10:1157651.

[150] LiY, QinS, DongL, et al. Long-term effects of Omicron BA.2 breakthrough infection on immunity-metabolism balance: a 6-month prospective study. Nat Commun. 2024;15(1):2444.

[151] ArfijantoMV, Asmarawati TP, BramantonoB, et al. Duration of SARS-CoV-2 RNA shedding is significantly influenced by disease severity, bilateral pulmonary infiltrates, antibiotic treatment, and diabetic status: consideration for isolation period. Pathophysiology. 2023;30(2):186-198.

[152] LiTZ, CaoZH, ChenY, et al. Duration of SARS-CoV-2 RNA shedding and factors associated with prolonged viral shedding in patients with COVID-19. J Med Virol. 2021;93(1):506-512.

[153] WangY, ChenR, HuF, et al. Transmission, viral kinetics and clinical characteristics of the emergent SARS-CoV-2 Delta VOC in Guangzhou, China. EClinicalMedicine. 2021;40:101129.

[154] HayJA, Kissler SM, FauverJR, et al. Quantifying the impact of immune history and variant on SARS-CoV-2 viral kinetics and infection rebound: a retrospective cohort study. eLife. 2022;11:e81849.

[155] ChenM, PekoszA, VillanoJS, et al. Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants. J Clin Invest. 2024;134(8).

[156] SeehusenF, ClarkJJ, SharmaP, et al. Neuroinvasion and neurotropism by SARS-CoV-2 variants in the K18-hACE2 mouse. Viruses. 2022;14(5):1020.

[157] PuhachO, MeyerB, EckerleI. SARS-CoV-2 viral load and shedding kinetics. Nat Rev Microbiol. 2023;21(3):147-161.

[158] ZubchenkoS, KrilI, NadizhkoO, Matsyura O, ChopyakV. Herpesvirus infections and post-COVID-19 manifestations: a pilot observational study. Rheumatol Int. 2022;42(9):1523-1530.

[159] SuY, YuanD, ChenDG, et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell. 2022;185(5):881-895.e2.

[160] GuptaS, DuttaA, ChakrabortyU, KumarR, DasD, RayBK. Post-COVID-19 HSV encephalitis: a review. QJM. 2022;115(4):222-227.

[161] ChenYC, HoCH, LiuTH, et al. Long-term risk of herpes zoster following COVID-19: a retrospective cohort study of 2 442 686 patients. J Med Virol. 2023;95(7):e28944.

[162] LehnerGF, KleinSJ, ZollerH, Peer A, BellmannR, JoannidisM. Correlation of interleukin-6 with Epstein-Barr virus levels in COVID-19. Crit Care. 2020;24(1):657.

[163] GoldJE, OkyayRA, LichtWE, Hurley DJ. Investigation of long COVID prevalence and its relationship to Epstein-Barr virus reactivation. Pathogens. 2021;10(6):763.

[164] Castanares-ZapateroD, Chalon P, KohnL, et al. Pathophysiology and mechanism of long COVID: a comprehensive review. Ann Med. 2022;54(1):1473-1487.

[165] ChenS, DengY, PanD. MicroRNA regulation of human herpesvirus latency. Viruses. 2022;14(6):1215.

[166] SausenD, BhuttaM, GalloE, Dahari H, BorensteinR. Stress-induced Epstein-Barr virus reactivation. Biomolecules. 2021;11(9):1380.

[167] ChenB, JulgB, MohandasS, Bradfute SB, RECOVER Mechanistic Pathways Task Force. Viral persistence, reactivation, and mechanisms of long COVID. eLife. 2023;12:e86015.

[168] ShikovaE, Reshkova V, Kumanovaа, et al. Cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome. J Med Virol. 2020;92(12):3682-3688.

[169] WongTL, Weitzer DJ. Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-A systemic review and comparison of clinical presentation and symptomatology. Medicina. 2021;57(5):418.

[170] SchreinerP, HarrerT, ScheibenbogenC, et al. Human herpesvirus-6 reactivation, mitochondrial fragmentation, and the coordination of antiviral and metabolic phenotypes in myalgic Encephalomyelitis/Chronic fatigue syndrome. Immunohorizons. 2020;4(4):201-215.

[171] WangEY, MaoT, KleinJ, et al. Diverse functional autoantibodies in patients with COVID-19. Nature. 2021;595(7866):283-288.

[172] ChangSE, FengA, MengW, et al. New-onset IgG autoantibodies in hospitalized patients with COVID-19. Nat Commun. 2021;12(1):5417.

[173] WallukatG, Hohberger B, WenzelK, et al. Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms. J Transl Autoimmun. 2021;4:100100.

[174] SotznyF, Filgueiras IS, KedorC, et al. Dysregulated autoantibodies targeting vaso-and immunoregulatory receptors in post COVID syndrome correlate with symptom severity. Front Immunol. 2022;13:981532.

[175] ThurnerL, FadleN, RegitzE, et al. Autoantibodies against SUMO1-DHX35 in long-COVID. J Transl Autoimmun. 2022;5:100171.

[176] JukemaBN, SmitK, HopmanMTE, et al. Neutrophil and eosinophil responses remain abnormal for several months in primary care patients with COVID-19 disease. Front Allergy. 2022;3:942699.

[177] Di CiaulaA, Liberale L, PortincasaP, et al. Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients. Eur J Clin Invest. 2024;54(4):e14155.

[178] HociniH, Wiedemann A, BlengioF, et al. Neutrophil activation and immune thrombosis profiles persist in convalescent COVID-19. J Clin Immunol. 2023;43(5):882-893.

[179] GeorgePM, ReedA, DesaiSR, et al. A persistent neutrophil-associated immune signature characterizes post-COVID-19 pulmonary sequelae. Sci Transl Med. 2022;14(671):eabo5795.

[180] SangalettiS, Tripodo C, ChiodoniC, et al. Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. Blood. 2012;120(15):3007-3018.

[181] ShafqatA, OmerMH, AlbalkhiI, et al. Neutrophil extracellular traps and long COVID. Front Immunol. 2023;14:1254310.

[182] ErlandsonKM, GengLN, SelvaggiCA, et al. Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort. Published online August 13, 2024.

[183] GalánM, Vigón L, FuertesD, et al. Persistent overactive cytotoxic immune response in a Spanish cohort of individuals with long-COVID: identification of diagnostic biomarkers. Front Immunol. 2022;13:848886.

[184] PretoriusE, VlokM, VenterC, 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.

[185] GristJT, Collier GJ, WaltersH, et al. Lung abnormalities detected with hyperpolarized 129Xe MRI in patients with long COVID. Radiology. 2022;305(3):709-717.

[186] ZhangK, LiuX, XuJ, et al. Deep-learning models for the detection and incidence prediction of chronic kidney disease and type 2 diabetes from retinal fundus images. Nat Biomed Eng. 2021;5(6):533-545.

[187] WangJ, GaoY, WangF, et al. Accurate estimation of biological age and its application in disease prediction using a multimodal image transformer system. Proc Natl Acad Sci U S A. 2024;121(3):e2308812120.

[188] GengLN, Bonilla H, HedlinH, et al. Nirmatrelvir-Ritonavir and symptoms in adults with postacute sequelae of SARS-CoV-2 infection: the STOP-PASC randomized clinical trial. JAMA Intern Med. 2024;184:1024.

[189] CongdonS, Narrowe Z, YoneN, et al. Nirmatrelvir/ritonavir and risk of long COVID symptoms: a retrospective cohort study. Sci Rep. 2023;13(1):19688.

[190] WangH, WeiY, HungCT, et al. Association of nirmatrelvir-ritonavir with post-acute sequelae and mortality in patients admitted to hospital with COVID-19: a retrospective cohort study. Lancet Infect Dis. 2024;24(10):1130-1140.

[191] ZiauddeenN, Gurdasani D, O’HaraME, et al. Characteristics and impact of long covid: findings from an online survey. PLoS One. 2022;17(3):e0264331.

[192] BatemanL, BestedAC, BonillaHF, et al. Myalgic Encephalomyelitis/Chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clin Proc. 2021;96(11):2861-2878.

[193] GlynneP, Tahmasebi N, GantV, GuptaR. Long COVID following mild SARS-CoV-2 infection: characteristic T cell alterations and response to antihistamines. J Investig Med. 2022;70(1):61-67.

[194] CarfìA, Bernabei R, LandiF. Persistent symptoms in patients after acute COVID-19. JAMA. 2020;324(6):603-605.

[195] BoltonMJ, Chapman BP, Van MarwijkH. Low-dose naltrexone as a treatment for chronic fatigue syndrome. BMJ Case Rep. 2020;13(1):e232502.

[196] HohbergerB, HarrerT, MardinC, et al. Case report: neutralization of autoantibodies targeting G-protein-coupled receptors improves capillary impairment and fatigue symptoms after COVID-19 infection. Front Med. 2021;8:754667.

[197] GeboKA, HeathSL, FukutaY, et al. Early antibody treatment, inflammation, and risk of post-COVID conditions. mBio. 2023;14(5):e0061823.

[198] RutschM, Buhr-Schinner H, GrossT, SchüllerPO, DeckR. Pulmonary rehabilitation in follow-up and inpatient rehabilitation for long COVID: twelve months of follow-up. Eur J Phys Rehabil Med. 2024;60(4):716-728.

[199] GottliebM, WangRC, YuH, et al. Severe fatigue and persistent symptoms at 3 months following severe acute respiratory syndrome coronavirus 2 infections during the pre-Delta, Delta, and Omicron time periods: a multicenter prospective cohort study. Clin Infect Dis. 2023;76(11):1930-1941.

[200] CatalàM, Mercadé-Besora N, KoldeR, et al. The effectiveness of COVID-19 vaccines to prevent long COVID symptoms: staggered cohort study of data from the UK, Spain, and Estonia. Lancet Respir Med. 2024;12(3):225-236.

[201] TrinhNT, Jödicke AM, CatalàM, et al. Effectiveness of COVID-19 vaccines to prevent long COVID: data from Norway. Lancet Respir Med. 2024;12(5):e33-e34.

[202] NotarteKI, Catahay JA, VelascoJV, et al. Impact of COVID-19 vaccination on the risk of developing long-COVID and on existing long-COVID symptoms: a systematic review. EClinicalMedicine. 2022;53:101624.

[203] MagliettaG, Diodati F, PuntoniM, et al. Prognostic factors for post-COVID-19 syndrome: a systematic review and Meta-analysis. J Clin Med. 2022;11(6):1541.

[204] CerviaC, Zurbuchen Y, TaeschlerP, et al. Immunoglobulin signature predicts risk of post-acute COVID-19 syndrome. Nat Commun. 2022;13(1):446.

RIGHTS & PERMISSIONS

2024 The Author(s). MedComm - Future Medicine published by John Wiley & Sons Australia, Ltd on behalf of Sichuan International Medical Exchange & Promotion Association (SCIMEA).