Study Approval
The study was approved by the Ethics Committee of University Hospital Essen (21-9998_1-KOBO, 20-9791-BO & 22-10581-BO). Written informed consent was obtained from all participants.
References
  1. Fainardi V, Meoli A, Chiopris G, Motta M, Skenderaj K, Grandinetti R, et al. Long COVID in Children and Adolescents. Life 2022;12:285. doi: 10.3390/life12020285
  2. Mehta NS, Mytton OT, Mullins EWS, Fowler TA, Falconer CL, Murphy OB, et al. SARS-CoV-2 (COVID-19): What Do We Know About Children? A Systematic Review. Clin Infect Dis 2020;71:2469–79. doi: 10.1093/cid/ciaa556
  3. Fialkowski A, Gernez Y, Arya P, Weinacht KG, Kinane TB, Yonker LM. Insight into the pediatric and adult dichotomy of COVID-19: Age-related differences in the immune response to SARS-CoV-2 infection. Pediatr Pulmonol 2020;55:2556–64. doi: 10.1002/ppul.24981
  4. Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, Rodriguez L, et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 2020;183:968-981.e7. doi: 10.1016/j.cell.2020.09.016
  5. Bogunovic D, Merad M. Children and SARS-CoV-2. Cell Host Microbe 2021;29:1040–2. doi: 10.1016/j.chom.2021.06.015
  6. Sorg AL, Becht S, Jank M, Armann J, von Both U, Hufnagel M, et al. Association of SARS-CoV-2 seropositivity with myalgic encephalomyelitis and/or chronic fatigue syndrome among children and adolescents in germany. JAMA Netw Open 2022;5:e2233454–e2233454. doi: 10.1001/jamanetworkopen.2022.33454.
  7. Borch L, Holm M, Knudsen M, Ellermann-Eriksen S, Hagstroem S. Long COVID symptoms and duration in SARS-CoV-2 positive children — a nationwide cohort study. Eur J Pediatr 2022;181:1597–607. doi: 10.1007/s00431-021-04345-z
  8. Leftin Dobkin SC, Collaco JM, McGrath-Morrow SA. Protracted respiratory findings in children post-SARS-CoV-2 infection. Pediatr Pulmonol 2021;56:3682–7. doi: 10.1002/ppul.25671.
  9. Ortona E, Malorni W. Long COVID: to investigate immunological mechanisms and sex/gender related aspects as fundamental steps for tailored therapy. Eur Respir J 2022;59:2102245. doi: 10.1183/13993003.02245-2021
  10. Rao S, Lee GM, Razzaghi H, Lorman V, Mejias A, Pajor NM, et al. Clinical Features and Burden of postacute sequelae of SARS-CoV-2 infection in children and adolescents. JAMA Pediatr 2022;176:1000–9. doi: 10.1001/jamapediatrics.2022.2800
  11. Lopez-Leon S, Wegman-Ostrosky T, Ayuzo del Valle NC, Perelman C, Sepulveda R, Rebolledo PA, et al. Long-COVID in children and adolescents: a systematic review and meta-analyses. Sci Rep 2022;12:9950. doi: 10.1038/s41598-022-13495-5
  12. Kikkenborg Berg S, Palm P, Nygaard U, Bundgaard H, Petersen MNS, Rosenkilde S, et al. Long COVID symptoms in SARS-CoV-2-positive children aged 0–14 years and matched controls in Denmark (LongCOVIDKidsDK): a national, cross-sectional study. Lancet Child Adolesc Health 2022;6:614–23. doi: 10.1016/S2352-4642(22)00154-7
  13. Michelen M, Manoharan L, Elkheir N, Cheng V, Dagens A, Hastie C, et al. Characterising long COVID: a living systematic review. BMJ Glob Health 2021;6:e005427. doi: 10.1136/bmjgh-2021-005427
  14. Funk AL, Kuppermann N, Florin TA, Tancredi DJ, Xie J, Kim K, et al. Post–COVID-19 conditions among children 90 days after sars-cov-2 infection. JAMA Netw Open 2022;5:e2223253–e2223253. doi: 10.1001/jamanetworkopen.2022.23253
  15. Su Y, Yuan D, Chen DG, Ng RH, Wang K, Choi J, et al. Multiple early factors anticipate post-acute COVID-19 sequelae. Cell 2022;185:881-895.e20. doi: 10.1016/j.cell.2022.01.014
  16. Grandjean L, Saso A, Torres Ortiz A, Lam T, Hatcher J, Thistlethwayte R, et al. Long-term persistence of spike protein antibody and predictive modeling of antibody dynamics after infection with severe acute respiratory syndrome coronavirus 2. Clin Infect Dis 2022;74:1220–9 doi: 10.1093/cid/ciab607
  17. Choutka J, Jansari V, Hornig M, Iwasaki A. Unexplained post-acute infection syndromes. Nat Med 2022;28:911–23. doi: 10.1038/s41591-022-01810-6
  18. Koczulla A, Ankermann T, Behrends U, Berlit P, Böing S, Brinkmann F, et al. S1-Leitlinie Post-COVID/Long-COVID. Pneumologie 2021;75:869-900. doi: 10.1055/a-1551-9734
  19. Venkatesan P. NICE guideline on long COVID. Lancet Respir Med. 2021;9:129. doi: 10.1016/S2213-2600(21)00031-X
  20. Brasseler M, Schönecker A, Steindor M, Della Marina A, Bruns N, Dogan B, et al. Development of restrictive eating disorders in children and adolescents with long-COVID-associated smell and taste dysfunction. Front Pediatr 2022;10:1022669. doi: 10.3389/fped.2022.1022669
  21. Thieme CJ, Anft M, Paniskaki K, Blazquez-Navarro A, Doevelaar A, Seibert FS, et al. Robust T cell response toward spike, membrane, and nucleocapsid SARS-CoV-2 Proteins is not associated with recovery in critical COVID-19 patients. Cell Rep Med 2020;1:100092. doi: 10.1016/j.xcrm.2020.100092.
  22. Paniskaki K, Anft M, Meister TL, Marheinecke C, Pfaender S, Skrzypczyk S, et al. Immune response in moderate to critical breakthrough COVID-19 infection after mRNA vaccination. Front Immunol 2022;13:816220. doi: 10.3389/fimmu.2022.816220
  23. Anft M, Paniskaki K, Blazquez-Navarro A, Doevelaar A, Seibert FS, Hölzer B, et al. COVID-19-induced ARDS is associated with decreased frequency of activated memory/effector T cells expressing CD11a++. Mol Ther 2020;28:2691–702. doi: 10.1016/j.ymthe.2020.10.001
  24. Loyal L, Braun J, Henze L, Kruse B, Dingeldey M, Reimer U, et al. Cross-reactive CD4 + T cells enhance SARS-CoV-2 immune responses upon infection and vaccination. Science 2021;374:eabh1823. doi: 10.1126/science.abh1823
  25. Paniskaki K, Konik MJ, Anft M, Meister TL, Marheinecke C, Pfaender S, et al. Superior humoral immunity in vaccinated SARS-CoV-2 convalescence as compared to SARS-COV-2 infection or vaccination. Front Immunol 2022;13:1031254. doi: 10.3389/fimmu.2022.1031254
  26. Kent SJ, Khoury DS, Reynaldi A, Juno JA, Wheatley AK, Stadler E, et al. Disentangling the relative importance of T cell responses in COVID-19: leading actors or supporting cast? Nat Rev Immunol 2022; 22:387-397. doi:10.1038/s41577-022-00716-1
  27. Finlay JB, Brann DH, Abi Hachem R, Jang DW, Oliva AD, Ko T, et al. Persistent post–COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium. Sci Transl Med 2022;14:eadd0484. doi: 10.1126/scitranslmed.add0484
  28. Cheon IS, Li C, Son YM, Goplen NP, Wu Y, Cassmann T, et al. Immune signatures underlying post-acute COVID-19 lung sequelae. Sci Immunol 2021;6:eabk1741. doi: 10.1126/sciimmunol.abk1741
  29. Phetsouphanh C, Darley DR, Wilson DB, Howe A, Munier CML, Patel SK, et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol 2022;23:210–6. doi: 10.1038/s41590-021-01113-x.
  30. Littlefield KM, Watson RO, Schneider JM, Neff CP, Yamada E, Zhang M, et al. SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2. PLoS Pathog 2022;18: e1010359. doi: 10.1371/journal.ppat.1010359
  31. Bacher P, Rosati E, Esser D, Martini GR, Saggau C, Schiminsky E, et al. Low-avidity CD4+ T cell responses to SARS-CoV-2 in unexposed individuals and humans with severe COVID-19. Immunity 2020;53:1258-1271.e5. doi: 10.1016/j.immuni.2020.11.016
  32. Paniskaki K, Konik MJ, Anft M, Heidecke H, Meister TL, Pfaender S, et al. Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19. Front Microbiol 2023;14:1196721. doi: 10.3389/fmicb.2023.1196721
  33. Durazo FA, Nicholas AA, Mahaffey JJ, Sova S, Evans JJ, Trivella JP, et al. Post–Covid-19 cholangiopathy—A new indication for liver transplantation: A case report. Transplant Proc. 2021;53:1132–7. doi: 10.1016/j.transproceed.2021.03.007
  34. Roth NC, Kim A, Vitkovski T, Xia J, Ramirez G, Bernstein D, et al. Post–COVID-19 Cholangiopathy: A Novel Entity. Am J Gastroenterol 2021;116:1077-1082. doi:10.14309/ajg.0000000000001154
  35. Cooper S, Tobar A, Konen O, Orenstein N, Kropach Gilad N, Landau YE, et al. Long COVID-19 liver manifestation in children. J Pediatr Gastroenterol Nutr 2022;75:244-251. doi: 10.1097/MPG.0000000000003521
  36. Acosta-Ampudia Y, Monsalve DM, Rojas M, Rodríguez Y, Zapata E, Ramírez-Santana C, et al. Persistent autoimmune activation and proinflammatory state in post-coronavirus disease 2019 syndrome. J Infect Dis 2022;225:2155–62. doi: 10.1093/infdis/jiac017
  37. Lee CH, Giuliani F. The role of inflammation in depression and fatigue. Front Immunol. 2019;10:1696. doi: 10.3389/fimmu.2019.01696
  38. Klimas NG, Broderick G, Fletcher MA. Biomarkers for chronic fatigue. Brain Behav Immun. 2012;26:1202–10. doi: 10.1016/j.bbi.2012.06.006
  39. Raison CL, Lin JMS, Reeves WC. Association of peripheral inflammatory markers with chronic fatigue in a population-based sample. Brain Behav Immun 2009;23:327–37. doi: 10.1016/j.bbi.2008.11.005
  40. Pedraz-Petrozzi B, Neumann E, Sammer G. Pro-inflammatory markers and fatigue in patients with depression: A case-control study. Sci Rep 2020;10:9494. doi: 10.1038/s41598-020-66532-6
  41. Fernández-Castañeda A, Lu P, Geraghty AC, Song E, Lee MH, Wood J, et al. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell 2022;185:2452-2468.e16. doi: 10.1016/j.cell.2022.06.008
  42. Etter MM, Martins TA, Kulsvehagen L, Pössnecker E, Duchemin W, Hogan S, et al. Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study. Nat Commun 2022;13:6777. doi:10.1038/s41467-022-34068-0
  43. Kiho S, Rameen J, Abhiroop C, Manan M, Carmen V, Kate M, et al. Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long COVID symptoms. Eur Respir J 2023;61:2200970. doi: 10.1183/13993003.00970-2022
Tables
Table 1: Demographic characteristics of the study cohorts