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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。
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確診後遺症免疫系統失調
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。
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確診後遺症血管問題和器官損傷
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。
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確診後遺症神經和認知系統
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。
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確診後遺症自律神經失調和相關疾病
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
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