長新冠可能有多種潛在病因，包括病毒殘留、免疫失調、微生物群落異常、自體免疫、血管內皮功能異常、腦幹和迷走神經異常等。許多研究還處於初步階段，需要進一步研究
新冠病毒是一種多系統疾病。根據對全球COVID-19病例的估算，確診後遺症已經影響了至少6,500萬人1，佔感染者的10%。由於許多未經記錄的病例，實際數字可能遠高於此。確診後遺症的發生率估計為非住院病例的10%至30%，住院病例的50%至70%2,3和接種疫苗的病例的10%至12%4,5。確診後遺症與各年齡段和急性病程嚴重程度有關，最高的診斷率在36至50歲之間，大多數確診後遺症病例是在非住院患者中出現的，他們的急性疾病輕微6，因為這個人群代表了整體COVID-19病例的大多數。目前有很多研究挑戰，如本文所述，仍有許多開放性問題，特別是有關病理生理學，有效治療和風險因素的問題。
已經有數百項生物醫學研究發現，許多患者在多個器官系統上經歷了數十種症狀7（圖1）。新冠確診後遺症包括多種不良結果，常見的新發疾病包括心血管疾病、血栓性和腦血管疾病8、2型糖尿病9、慢性疲勞症/慢性疲勞綜合症（ME/CFS）10,11和自主神經失調，尤其是直立性心動過速綜合症（POTS）12（圖2）。症狀可能持續多年13，特別是在新發的ME/CFS和自主神經失調症例中預計是終身性的14。
確診後遺症是指感染新冠病毒後，持續經歷症狀超過12週的人。許多確診後遺症的患者無法返回工作崗位，這導致勞動力
短缺。目前還沒有有效治療方法，因為新冠確診後遺症可能有多種潛在病因，包括病毒殘留、免疫失調、微生物群落異常、自體免疫、血管內皮功能異常、腦幹和迷走神經異常等。許多研究還處於初步階段，需要進一步研究。患有確診後遺症的風險因素可能包括女性、2型糖尿病、EBV復活、特定自身抗體、結締組織疾病等。此外，某些族裔人群（如西班牙或拉丁裔）和經濟弱勢人群也可能面臨更高的風險。由於許多確診後遺症患者最初未住院治療，我們的研究重點在於對未住院和沒有呼吸道疾病證據的患者進行研究。因為確診後遺症和其他後病毒性疾病（如慢性疲勞症候群）有類似的病理和表現特徵，所以我們需要更多的研究來探究這些共同點。本文將探討目前關於確診後遺症的知識以及人們對它的誤解，以及需要進一步研究的領域。
(點擊查閱文獻)
16. Swank Z, et al. Persistent circulating severe acute respiratory syndrome coronavirus 2 spike is associated with post-acute coronavirus disease 2019 sequelae. Clin. Infect. Dis. 2022 doi: 10.1093/cid/ciac722. [PubMed] [CrossRef] [Google Scholar]
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: 10.3389/fmicb.2021.698169. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
18. Klein, J. et al. Distinguishing features of Long COVID identified through immune profiling. Preprint at medRxiv10.1101/2022.08.09.22278592 (2022).
19. Glynne P, Tahmasebi N, Gant V, Gupta R. Long COVID following mild SARS-CoV-2 infection: characteristic T cell alterations and response to antihistamines. J. Investig. Med. 2022;70:61–67. doi: 10.1136/jim-2021-002051. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
20. Phetsouphanh C, et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat. Immunol. 2022;23:210–216. doi: 10.1038/s41590-021-01113-x. [PubMed] [CrossRef] [Google Scholar]
21. Zubchenko S, Kril I, Nadizhko O, Matsyura O, Chopyak V. Herpesvirus infections and post-COVID-19 manifestations: a pilot observational study. Rheumatol. Int. 2022 doi: 10.1007/s00296-022-05146-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. Peluso MJ, et al. Evidence of recent Epstein-Barr virus reactivation in individuals experiencing Long COVID. Preprint at medRxiv. 2022 doi: 10.1101/2022.06.21.22276660. [CrossRef] [Google Scholar]
23. Yeoh YK, et al. Gut microbiota composition reflects disease severity and dysfunctional immune responses in patients with COVID-19. Gut. 2021;70:698–706. doi: 10.1136/gutjnl-2020-323020. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
24. Liu Q, et al. Gut microbiota dynamics in a prospective cohort of patients with post-acute COVID-19 syndrome. Gut. 2022;71:544–552. doi: 10.1136/gutjnl-2021-325989. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
25. Mendes de Almeida V. Gut microbiota from patients with mild COVID-19 cause alterations in mice that resemble post-COVID syndrome. Res. Sq. 2022 doi: 10.21203/rs.3.rs-1756189/v1. [CrossRef] [Google Scholar]
26. Wallukat G, et al. Functional autoantibodies against G-protein coupled receptors in patients with persistent long-COVID-19 symptoms. J. Transl Autoimmun. 2021;4:100100. doi: 10.1016/j.jtauto.2021.100100. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
27. Su Y, 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. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
28. Arthur JM, et al. Development of ACE2 autoantibodies after SARS-CoV-2 infection. PLoS ONE. 2021;16:e0257016. doi: 10.1371/journal.pone.0257016. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
29. Haffke M, et al. Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS) J. Transl Med. 2022;20:138. doi: 10.1186/s12967-022-03346-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
30. Charfeddine S. Long COVID 19 syndrome: is it related to microcirculation and endothelial dysfunction? Insights from TUN-EndCOV study. Front. Cardiovasc. Med. 2021 doi: 10.3389/fcvm.2021.745758. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
31. Pretorius E, et al. Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/post-acute sequelae of COVID-19 (PASC) Cardiovasc. Diabetol. 2022;21:148. doi: 10.1186/s12933-022-01579-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
32. Spudich S, Nath A. Nervous system consequences of COVID-19. Science. 2022;375:267–269. doi: 10.1126/science.abm2052. [PubMed] [CrossRef] [Google Scholar]
33. Renz-Polster H, Tremblay M-E, Bienzle D, Fischer JE. The pathobiology of myalgic encephalomyelitis/chronic fatigue syndrome: the case for neuroglial failure. Front. Cell. Neurosci. 2022;16:888232. doi: 10.3389/fncel.2022.888232. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
34. Merzon E, et al. Clinical and socio-demographic variables associated with the diagnosis of long COVID syndrome in youth: a population-based study. Int. J. Environ. Res. Public Health. 2022;19:5993. doi: 10.3390/ijerph19105993. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
35. CDC. Long COVID - household pulse survey - COVID-19. CDChttps://www.cdc.gov/nchs/covid19/pulse/long-covid.htm (2022).
36. Williamson AE, Tydeman F, Miners A, Pyper K, Martineau AR. Short-term and long-term impacts of COVID-19 on economic vulnerability: a population-based longitudinal study (COVIDENCE UK) BMJ Open. 2022;12:e065083. doi: 10.1136/bmjopen-2022-065083. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
37. Ziauddeen N, et al. Characteristics and impact of Long Covid: findings from an online survey. PLoS ONE. 2022;17:e0264331. doi: 10.1371/journal.pone.0264331. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
確診後遺症免疫系統失調
長新冠長期症狀研究中發現免疫系統失調，包括疲憊T細胞、減少CD4+和CD8+效應器記憶細胞數量、以及中央記憶細胞上的PD1表達升高，持續至少13個月。研究還報告了高度活化的固有免疫細胞、缺乏原生T和B細胞、以及持續至少8個月的I型和III型干擾素表達（干擾素-β和IFNλ1）。與未感染和感染但沒有長期症狀的人相比，長新冠患者的非經典單核細胞、活化的B細胞、雙陰性B細胞和分泌IL-4和IL-6的CD4+ T細胞數量增加，而常規樹突細胞和疲憊T細胞數量減少，皮質醇水平低，持續至少14個月。細胞毒性T細胞的擴增被發現與長新冠胃腸道表現有關。其他研究發現了細胞激素水平的升高，特別是IL-1β、IL-6、TNF和IP10，以及一項最近的預印本報告了與認知功能障礙相關的CCL11水平持續升高。自身抗體的水平也被發現升高，包括對ACE2（SARS-CoV-2進入的受體）、β2-腎上腺素受體、肌動蛋白M2受體、血管緊張素II AT1受體和血管緊張素1-7 MAS受體的自身抗體。多項研究顯示，在急性COVID-19的初期，低或無SARS-CoV-2抗體產生和其他免疫反應不足，包括低IgG基線水平、低受體結合域和尖突蛋白特異性記憶B細胞、核鞘IgG的低水平和尖突蛋白特異性IgG的低峰值，預示著可能在6-7個月後發生長期症狀。
38. Choutka J, Jansari V, Hornig M, Iwasaki A. Unexplained post-acute infection syndromes. Nat. Med. 2022;28:911–923. doi: 10.1038/s41591-022-01810-6. [PubMed] [CrossRef] [Google Scholar]
39. Komaroff AL, Lipkin WI. Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of postacute COVID-19 syndrome. Trends Mol. Med. 2021;27:895–906. doi: 10.1016/j.molmed.2021.06.002. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
40. Schultheiß C, et al. From online data collection to identification of disease mechanisms: the IL-1ß, IL-6 and TNF-α cytokine triad is associated with post-acute sequelae of COVID-19 in a digital research cohort. SSRN. 2021 doi: 10.2139/ssrn.3963839. [CrossRef] [Google Scholar]
41. Peluso MJ, 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;224:1839–1848. doi: 10.1093/infdis/jiab490. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
42. Fernández-Castañeda A, et al. Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain. bioRxiv. 2022 doi: 10.1101/2022.01.07.475453. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
43. Hornig M, et al. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Sci. Adv. 2015;1:e1400121. doi: 10.1126/sciadv.1400121. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
44. Wang EY, et al. Diverse functional autoantibodies in patients with COVID-19. Nature. 2021;595:283–288. doi: 10.1038/s41586-021-03631-y. [PubMed] [CrossRef] [Google Scholar]
45. Shikova E, et al. Cytomegalovirus, Epstein-Barr virus, and human herpesvirus-6 infections in patients with myalgic еncephalomyelitis/chronic fatigue syndrome. J. Med. Virol. 2020;92:3682–3688. doi: 10.1002/jmv.25744. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
46. Schreiner P, et al. Human herpesvirus-6 reactivation, mitochondrial fragmentation, and the coordination of antiviral and metabolic phenotypes in myalgic encephalomyelitis/chronic fatigue syndrome. Immunohorizons. 2020;4:201–215. doi: 10.4049/immunohorizons.2000006. [PubMed] [CrossRef] [Google Scholar]
47. García-Abellán J, 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;41:1490–1501. doi: 10.1007/s10875-021-01083-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
48. Augustin M, et al. Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study. Lancet Reg. Health Eur. 2021;6:100122. doi: 10.1016/j.lanepe.2021.100122. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
49. Talla A, et al. Longitudinal immune dynamics of mild COVID-19 define signatures of recovery and persistence. bioRxiv. 2022 doi: 10.1101/2021.05.26.442666. [CrossRef] [Google Scholar]
50. Peluso MJ, et al. Long-term SARS-CoV-2-specific immune and inflammatory responses in individuals recovering from COVID-19 with and without post-acute symptoms. Cell Rep. 2021;36:109518. doi: 10.1016/j.celrep.2021.109518. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
51. Hu F, et al. A compromised specific humoral immune response against the SARS-CoV-2 receptor-binding domain is related to viral persistence and periodic shedding in the gastrointestinal tract. Cell. Mol. Immunol. 2020;17:1119–1125. doi: 10.1038/s41423-020-00550-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
52. Korte W, et al. SARS-CoV-2 IgG and IgA antibody response is gender dependent; and IgG antibodies rapidly decline early on. J. Infect. 2021;82:e11–e14. doi: 10.1016/j.jinf.2020.08.032. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
53. Jo W, et al. A two-phase, single cohort study of COVID-19 antibody sera-surveillance. Ann. Epidemiol. Public Health. 2021;4:1055. doi: 10.33582/2639-4391/1055. [CrossRef] [Google Scholar]
54. Nomura Y, et al. Attenuation of antibody titers from 3 to 6 months after the second dose of the BNT162b2 vaccine depends on sex, with age and smoking risk factors for lower antibody titers at 6 months. Vaccines. 2021;9:1500. doi: 10.3390/vaccines9121500. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
55. Tejerina F, 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;22:211. doi: 10.1186/s12879-022-07153-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
56. Goh, D. et al. Persistence of residual SARS-CoV-2 viral antigen and RNA in tissues of patients with long COVID-19. Preprint at https://www.researchsquare.com/article/rs-1379777/v1 (2022).
57. Ceulemans LJ, et al. Persistence of SARS-CoV-2 RNA in lung tissue after mild COVID-19. Lancet Respir. Med. 2021;9:e78–e79. doi: 10.1016/S2213-2600(21)00240-X. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
58. Gaebler C, et al. Evolution of antibody immunity to SARS-CoV-2. Nature. 2021;591:639–644. doi: 10.1038/s41586-021-03207-w. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
確診後遺症血管問題和器官損傷
儘管COVID-19最初被認為是一種呼吸系統疾病，但SARS-CoV-2具有損害許多器官系統的能力。已經展示了跨越不同組織的損害主要歸因於免疫介導反應和炎症，而不是病毒直接感染細胞。循環系統的擾亂包括內皮功能障礙和隨後的下游影響，以及深靜脈血栓、肺栓塞和出血事件的風險增加29,30,62。在急性COVID-19和長期COVID中檢測到的微小血栓貢獻了血栓形成63並且是一個有吸引力的診斷和治療靶點。在長期COVID中還發現了血液細胞的大小和硬度的長期變化，這可能影響氧氣供應64。與對照組相比，長期COVID患者發現了長達18個月的血管密度的持久性減少，特別是影響小毛細血管65。一項研究發現長期COVID中升高的血管轉化血液生物標記還發現，血管生成標記ANG1和P-selectin都具有高敏感性和特異性，可用於預測長期COVID狀態66。
對美國退伍軍人事務部數據庫（VA數據）的分析，包括150,000多名SARS-CoV-2感染1年後的個體，顯示出各種心血管疾病的明顯風險增加，包括心力衰竭、心律失常和中風，與COVID-19初期嚴重程度無關8（圖2）。心臟核磁共振研究顯示，在100名先前接受COVID-19治療的個體中（平均感染後71天調查），78％存在心臟損傷，以及58％的長期COVID患者（感染12個月後調查）也存在心臟異常68，進一步證實了心臟異常的持久性。
多項研究顯示COVID-19與多器官損傷有關。一項前瞻性研究針對低風險人群，觀察了心臟、肺、肝、腎臟、胰臟和脾臟，發現201名患者中有70％的人至少損傷了一個器官，29％的人有多器官損傷。同一研究小組進行的一項1年追蹤研究包括536名參與者，發現59％的人損傷了單個器官，27％的人有多器官損傷。一項專門針對腎臟的VA數據研究，包括超過89,000名COVID-19患者，發現患者有增加的不良腎臟結局風險。另一個VA數據分析，包括超過181,000名COVID-19患者，發現感染也增加了2型糖尿病的風險（圖2）。長COVID的患者所經歷的器官損傷是持久的，長期效應仍未知。
59. Menuchin-Lasowski Y, et al. SARS-CoV-2 infects and replicates in photoreceptor and retinal ganglion cells of human retinal organoids. Stem Cell Rep. 2022;17:789–803. doi: 10.1016/j.stemcr.2022.02.015. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
60. Cheung CCL, et al. Residual SARS-CoV-2 viral antigens detected in GI and hepatic tissues from five recovered patients with COVID-19. Gut. 2022;71:226–229. doi: 10.1136/gutjnl-2021-324280. [PubMed] [CrossRef] [Google Scholar]
61. Natarajan A, et al. Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection. Med. 2022;3:371–387.e9. doi: 10.1016/j.medj.2022.04.001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
62. Katsoularis I, et al. Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study. BMJ. 2022;377:e069590. doi: 10.1136/bmj-2021-069590. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
63. Pretorius E, 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;20:172. doi: 10.1186/s12933-021-01359-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
64. Kubánková M, et al. Physical phenotype of blood cells is altered in COVID-19. Biophys. J. 2021;120:2838–2847. doi: 10.1016/j.bpj.2021.05.025. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
65. Osiaevi I, et al. Persistent capillary rarefication in long COVID syndrome. Angiogenesis. 2022 doi: 10.1007/s10456-022-09850-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
66. Patel MA, et al. Elevated vascular transformation blood biomarkers in long-COVID indicate angiogenesis as a key pathophysiological mechanism. Mol. Med. 2022;28:122. doi: 10.1186/s10020-022-00548-8. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
67. Puntmann VO, et al. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19) JAMA Cardiol. 2020;5:1265–1273. doi: 10.1001/jamacardio.2020.3557. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
68. Roca-Fernández A, et al. Cardiac impairment in Long Covid 1-year post-SARS-CoV-2 infection. Eur. Heart J. 2022;43:ehac544.219. doi: 10.1093/eurheartj/ehac544.219. [CrossRef] [Google Scholar]
69. Dennis A, et al. Multiorgan impairment in low-risk individuals with post-COVID-19 syndrome: a prospective, community-based study. BMJ Open. 2021;11:e048391. doi: 10.1136/bmjopen-2020-048391. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
70. Dennis, A. et al. Multi-organ impairment and Long COVID: a 1-year prospective, longitudinal cohort study. Preprint at medRxiv10.1101/2022.03.18.22272607 (2022). [PubMed]
71. Bowe B, Xie Y, Xu E, Al-Aly Z. Kidney outcomes in Long COVID. J. Am. Soc. Nephrol. 2021;32:2851–2862. doi: 10.1681/ASN.2021060734. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
確診後遺症神經和認知系統
神經和認知症狀是長新冠的主要特徵，包括感覺運動症狀、記憶喪失、認知障礙、異常感覺、頭暈和平衡問題、對光和噪音的敏感度、失去（或虛假的）嗅覺或味覺，以及自主神經功能失調，通常會影響日常生活。在一項荟萃分析中，在感染後12週，COVID-19患者中有32％的人出現疲勞，22％的人出現認知障礙。長新冠的認知障礙是令人崩潰的，其程度相當於英國酒駕限制或10年的認知老化，而且可能隨著時間的推移而增加。在一項研究中，發現感染後2個月16％的患者出現認知障礙，感染後12個月26％的患者出現認知障礙。在長新冠中已經發現了Kynurenine途徑的激活，尤其是存在代謝物吲哚醋酸，3-羥基蒽醌酸和Kynurenine，與認知障礙有關。此外，已發現從COVID-19康復的個體中出現認知障礙，且當使用客觀測量而非主觀測量時，認知障礙的發生率較高，這表明某些認知障礙患者可能沒有認識到和/或報告他們的障礙。認知障礙是一種獨立於焦慮和抑鬱等心理健康狀況的特徵，並在住院和非住院患者中發生率相似。超過130萬名COVID-19患者的報告顯示，像焦慮和抑鬱等心理健康狀況隨著時間的推移恢復正常，但認知障礙（腦霧）、癲癇、痴呆、精神病和其他神經認知疾病的風險在至少2年內持續增加。
這些神經病理的可能機制包括神經炎症、血管凝血和內皮功能障礙對血管的損傷，以及神經元損傷。研究發現長期新冠肺炎患者存在類似阿茲海默症信號、自聚集成淀粉樣凝聚物的肽對神經元有毒、廣泛的神經炎症、與特定症狀相關的大腦和腦幹代謝降低，以及長期新冠肺炎患者的脊髓液異常發現以及年輕人與神經症狀延遲發生之間的聯繫。長期新冠肺炎患者報告了多種神經病理，包括多種細胞系的失調和髓鞘損失。
在長新冠患者中，眼睛方面的病變包括角膜小神經纖維損失和樹突細胞密度增加，並且出現明顯的瞳孔對光反應異常和視網膜微循環受損。SARS-CoV-2病毒可感染並在視網膜和腦器官構造中繁殖。其他長新冠症狀包括視網膜出血、棉絮狀斑點和視網膜靜脈阻塞。
在小鼠輕度感染SARS-CoV-2的模型中，發現了微神經膠細胞反應和CCL11水平升高，後者與認知功能障礙和神經發生障礙有關。倉鼠模型表現出持續的炎症狀態，涉及T細胞和骨髓激活、產生促炎細胞因子和干擾素反應，這些都與倉鼠的焦慮和類抑鬱行為有關，並在復原COVID-19的人類組織中發現了類似的轉錄標誌。輕症非人類靈長類動物感染後顯示出神經炎症、神經元損傷和凋亡、腦微出血以及慢性缺氧和腦缺氧等。
最近的報告顯示，與對照組相比，患有長新冠的患者血液中的皮質醇水平低，症狀持續超過1年以上18,27。腎上腺腺體低皮質醇產量應該由垂體腺分泌腎上腺皮質刺激素（ACTH）的產量增加來補償，但事實並非如此，這表明下視丘-垂體-腎上腺軸功能障礙。這也可能反映潛在的神經炎症過程。
72. Almufarrij I, Munro KJ. One year on: an updated systematic review of SARS-CoV-2, COVID-19 and audio-vestibular symptoms. Int. J. Audiol. 2021;60:935–945. doi: 10.1080/14992027.2021.1896793. [PubMed] [CrossRef] [Google Scholar]
73. Holdsworth DA, et al. Comprehensive clinical assessment identifies specific neurocognitive deficits in working-age patients with long-COVID. PLoS ONE. 2022;17:e0267392. doi: 10.1371/journal.pone.0267392. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
74. Cysique, L. A. et al. Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study. Preprint at medRxiv10.1101/2022.06.07.22276020 (2022).
75. Crivelli L, et al. Changes in cognitive functioning after COVID-19: a systematic review and meta-analysis. Alzheimers Dement. 2022;18:1047–1066. doi: 10.1002/alz.12644. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
76. Woo MS, et al. Frequent neurocognitive deficits after recovery from mild COVID-19. Brain Commun. 2020;2:fcaa205. doi: 10.1093/braincomms/fcaa205. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
77. Taquet M, et al. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients. Lancet Psychiatry. 2022;9:815–827. doi: 10.1016/S2215-0366(22)00260-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
78. Reiken S, et al. Alzheimer’s-like signaling in brains of COVID-19 patients. Alzheimers Dement. 2022;18:955–965. doi: 10.1002/alz.12558. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
79. Charnley M, et al. Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19. Nat. Commun. 2022;13:3387. doi: 10.1038/s41467-022-30932-1. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
80. Visser, D. et al. Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET. Preprint at medRxiv10.1101/2022.06.02.22275916 (2022).
81. Guedj E, et al. 18F-FDG brain PET hypometabolism in patients with long COVID. Eur. J. Nucl. Med. Mol. Imaging. 2021;48:2823–2833. doi: 10.1007/s00259-021-05215-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
82. Hugon J, et al. Cognitive decline and brainstem hypometabolism in long COVID: a case series. Brain Behav. 2022;12:e2513. doi: 10.1002/brb3.2513. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
83. Apple AC, et al. Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19. Ann. Clin. Transl Neurol. 2022;9:221–226. doi: 10.1002/acn3.51498. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
84. Douaud G, et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. 2022;604:697–707. doi: 10.1038/s41586-022-04569-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
85. Peluso MJ, et al. SARS-CoV-2 and mitochondrial proteins in neural-derived exosomes of COVID-19. Ann. Neurol. 2022;91:772–781. doi: 10.1002/ana.26350. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
86. Villaume WA. Marginal BH4 deficiencies, iNOS, and self-perpetuating oxidative stress in post-acute sequelae of Covid-19. Med. Hypotheses. 2022;163:110842. doi: 10.1016/j.mehy.2022.110842. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
87. Bitirgen G, et al. Corneal confocal microscopy identifies corneal nerve fibre loss and increased dendritic cells in patients with long COVID. Br. J. Ophthalmol. 2021 doi: 10.1136/bjophthalmol-2021-319450. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
88. Barros A, et al. Small fiber neuropathy in the cornea of Covid-19 patients associated with the generation of ocular surface disease. Ocul. Surf. 2022;23:40–48. doi: 10.1016/j.jtos.2021.10.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
89. Bitirgen G, et al. Abnormal quantitative pupillary light responses following COVID-19. Int. Ophthalmol. 2022 doi: 10.1007/s10792-022-02275-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
90. Mardin CY, et al. Possible impact of functional active GPCR-autoantibodies on retinal microcirculation in long-COVID. Invest. Ophthalmol. Vis. Sci. 2022;63:3315–F0124. [Google Scholar]
91. Zhang B-Z, et al. SARS-CoV-2 infects human neural progenitor cells and brain organoids. Cell Res. 2020;30:928–931. doi: 10.1038/s41422-020-0390-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
92. Sen S, et al. Retinal manifestations in patients with SARS-CoV-2 infection and pathogenetic implications: a systematic review. Int. Ophthalmol. 2022;42:323–336. doi: 10.1007/s10792-021-01996-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
確診後遺症自律神經失調和相關疾病
長新冠是一種多系統神經免疫疾病，發病通常在病毒或細菌感染後出現。診斷標準包括在至少6個月的時間裡，“在職業、教育、社交或個人活動方面，有實質性的能力減少或受損”，並且伴隨著深度疲勞，休息也無法緩解，以及體力過度消耗後的不適、無法恢復的睡眠和認知障礙或直立性不耐受症狀（或兩者兼有）95。高達75％的患有長新冠的人無法全職工作，25％患有嚴重的長新冠，這通常意味著他們需要臥床休息，對感官刺激非常敏感，並且需要他人照顧96。在ME/CFS中有大量的生物醫學研究發現97,98，儘管這些研究結果並不為其他領域的研究人員和臨床醫生所知。
許多研究人員已經評論了長新冠和長期後遺症的相似之處99; 約有一半的患有長期後遺症的人估計符合ME/CFS的診斷標準10,11,29,100，在測量後運動誘發的惡化症狀時，大多數患有長期後遺症的人報告出現後運動誘發的惡化症狀7,100。一項關於長期後遺症和ME/CFS患者的直立壓力的研究發現，這兩組人群相比健康人群，具有相似的血流動力學、症狀和認知異常101。重要的是，ME/CFS應該起源於SARS-CoV-2感染並不令人意外，因為在一項研究中，SARS-CoV感染幸存者中有27.1％的人在發病4年後符合ME/CFS的診斷標準102
93. Frere JJ, et al. SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery. Sci. Transl Med. 2022;14:eabq3059. doi: 10.1126/scitranslmed.abq3059. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
94. Rutkai I, et al. Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates. Nat. Commun. 2022;13:1745. doi: 10.1038/s41467-022-29440-z. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
95. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Board on the Health of Select Populations, & Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness (National Academies Press, 2015). [PubMed]
96. Bateman L, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: essentials of diagnosis and management. Mayo Clin. Proc. 2021;96:2861–2878. doi: 10.1016/j.mayocp.2021.07.004. [PubMed] [CrossRef] [Google Scholar]
97. The ME Association. Index of ME/CFS published research - Nov 2022. 224 Index of ME/CFS Published Research. The ME Associationhttps://meassociation.org.uk/ (2022).
98. Seltzer, J. & Thomas, J. ME Research Summary 2019 (The ME Association, 2019).
99. Wong TL, Weitzer DJ. Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-a systemic review and comparison of clinical presentation and symptomatology. Med. (Kaunas.) 2021;57:418. [PMC free article] [PubMed] [Google Scholar]
100. Twomey R, et al. Chronic fatigue and postexertional malaise in people living with Long COVID: an observational study. Phys. Ther. 2022;102:pzac005. doi: 10.1093/ptj/pzac005. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
101. Vernon SD, et al. Orthostatic challenge causes distinctive symptomatic, hemodynamic and cognitive responses in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. Front. Med. 2022;9:917019. doi: 10.3389/fmed.2022.917019. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
102. Lam MH-B, et al. Mental morbidities and chronic fatigue in severe acute respiratory syndrome survivors: long-term follow-up. Arch. Intern. Med. 2009;169:2142–2147. doi: 10.1001/archinternmed.2009.384. [PubMed] [CrossRef] [Google Scholar]
103. Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO2peak indicates functional impairment. J. Transl Med. 2014;12:104. doi: 10.1186/1479-5876-12-104. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
104. Saha AK, et al. Erythrocyte deformability as a potential biomarker for chronic fatigue syndrome. Blood. 2018;132:4874. doi: 10.1182/blood-2018-99-117260. [CrossRef] [Google Scholar]
105. Díaz-Resendiz KJG, et al. Loss of mitochondrial membrane potential (ΔΨm) in leucocytes as post-COVID-19 sequelae. J. Leukoc. Biol. 2022;112:23–29. doi: 10.1002/JLB.3MA0322-279RRR. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
106. Pozzi A. COVID-19 and mitochondrial non-coding RNAs: new insights from published data. Front. Physiol. 2022;12:805005. doi: 10.3389/fphys.2021.805005. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
107. Guntur VP, et al. Signatures of mitochondrial dysfunction and impaired fatty acid metabolism in plasma of patients with post-acute sequelae of COVID-19 (PASC) Metabolites. 2022;12:1026. doi: 10.3390/metabo12111026. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
108. Paul BD, Lemle MD, Komaroff AL, Snyder SH. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome. Proc. Natl Acad. Sci. USA. 2021;118:e2024358118. doi: 10.1073/pnas.2024358118. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
109. Wright J, Astill SL, Sivan M. The relationship between physical activity and Long COVID: a cross-sectional study. Int. J. Environ. Res. Public Health. 2022;19:5093. doi: 10.3390/ijerph19095093. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
110. Heerdt PM, Shelley B, Singh I. Impaired systemic oxygen extraction long after mild COVID-19: potential perioperative implications. Br. J. Anaesth. 2022;128:e246–e249. doi: 10.1016/j.bja.2021.12.036. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
111. Novak P, et al. Multisystem involvement in post-acute sequelae of coronavirus disease 19. Ann. Neurol. 2022;91:367–379. doi: 10.1002/ana.26286. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
112. Holmes E, et al. Incomplete systemic recovery and metabolic phenoreversion in post-acute-phase nonhospitalized COVID-19 patients: implications for assessment of post-acute COVID-19 syndrome. J. Proteome Res. 2021;20:3315–3329. doi: 10.1021/acs.jproteome.1c00224. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
113. van Campen CLMC, Visser FC. Orthostatic intolerance in long-haul COVID after SARS-CoV-2: a case-control comparison with post-EBV and insidious-onset myalgic encephalomyelitis/chronic fatigue syndrome patients. Healthcare. 2022;10:2058. doi: 10.3390/healthcare10102058. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
114. van Campen CLMC, Visser FC. Long-Haul COVID patients: prevalence of POTS are reduced but cerebral blood flow abnormalities remain abnormal with longer disease duration. Healthcare. 2022;10:2105. doi: 10.3390/healthcare10102105. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
115. Nunes JM, Kruger A, Proal A, Kell DB, Pretorius E. The occurrence of hyperactivated platelets and fibrinaloid microclots in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Pharmaceuticals. 2022;15:931. doi: 10.3390/ph15080931. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
116. Hoad A, Spickett G, Elliott J, Newton J. Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome. QJM. 2008;101:961–965. doi: 10.1093/qjmed/hcn123. [PubMed] [CrossRef] [Google Scholar]
117. Shaw BH, et al. The face of postural tachycardia syndrome – insights from a large cross‐sectional online community‐based survey. J. Intern. Med. 2019;286:438–448. doi: 10.1111/joim.12895. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
118. Raj SR, et al. Postural orthostatic tachycardia syndrome (POTS): priorities for POTS care and research from a 2019 National Institutes of Health expert consensus meeting - part 2. Auton. Neurosci. Basic. Clin. 2021;235:102836. doi: 10.1016/j.autneu.2021.102836. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
119. Oaklander AL, et al. Peripheral neuropathy evaluations of patients with prolonged Long COVID. Neurol. Neuroimmunol. Neuroinflamm. 2022;9:e1146. doi: 10.1212/NXI.0000000000001146. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
120. Larsen NW, et al. Characterization of autonomic symptom burden in long COVID: a global survey of 2,314 adults. Front. Neurol. 2022;13:1012668. doi: 10.3389/fneur.2022.1012668. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
121. Weinstock LB, et al. Mast cell activation symptoms are prevalent in Long-COVID. Int. J. Infect. Dis. 2021;112:217–226. doi: 10.1016/j.ijid.2021.09.043. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
122. Boneva RS, et al. Endometriosis as a comorbid condition in chronic fatigue syndrome (CFS): secondary analysis of data from a CFS case-control study. Front. Pediatr. 2019;7:195. doi: 10.3389/fped.2019.00195. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
123. Bragée, B. et al. Signs of intracranial hypertension, hypermobility, and craniocervical obstructions in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Front. Neurol. 11, (2020). [PMC free article] [PubMed]