Holmes Elaine, Wist Julien, Masuda Reika, Lodge Samantha, Nitschke Philipp, Kimhofer Torben, Loo Ruey Leng, Begum Sofina, Boughton Berin, Yang Rongchang, Morillon Aude-Claire, Chin Sung-Tong, Hall Drew, Ryan Monique, Bong Sze-How, Gay Melvin, Edgar Dale W, Lindon John C, Richards Toby, Yeap Bu B, Pettersson Sven, Spraul Manfred, Schaefer Hartmut, Lawler Nathan G, Gray Nicola, Whiley Luke, Nicholson Jeremy K
Australian National Phenome Centre, Health Futures Institute, Murdoch University, Harry Perkins Building, 5 Robin Warren Drive, Perth, WA 6150, Australia.
Center for Computational and Systems Medicine, Health Futures Institute, Murdoch University, 5 Robin Warren Drive, Perth, WA 6150, Australia.
J Proteome Res. 2021 Jun 4;20(6):3315-3329. doi: 10.1021/acs.jproteome.1c00224. Epub 2021 May 19.
We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized COVID-19 patients and the possible biochemical sequelae of "Post-Acute COVID-19 Syndrome", colloquially known as long-COVID. Blood samples were taken from patients ca. 3 months after acute COVID-19 infection with further assessment of symptoms at 6 months. Some 57% of the patients had one or more persistent symptoms including respiratory-related symptoms like cough, dyspnea, and rhinorrhea or other nonrespiratory symptoms including chronic fatigue, anosmia, myalgia, or joint pain. Plasma samples were quantitatively analyzed for lipoproteins, glycoproteins, amino acids, biogenic amines, and tryptophan pathway intermediates using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Metabolic data for the follow-up patients ( = 27) were compared with controls ( = 41) and hospitalized severe acute respiratory syndrome SARS-CoV-2 positive patients ( = 18, with multiple time-points). Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID-19 biomarker signatures. Several parameters were persistently perturbed, e.g., elevated taurine ( = 3.6 × 10 versus controls) and reduced glutamine/glutamate ratio ( = 6.95 × 10 versus controls), indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function. Some parameters showed near-complete normalization, e.g., the plasma apolipoprotein B100/A1 ratio was similar to that of healthy controls but significantly lower ( = 4.2 × 10) than post-acute COVID-19 patients, reflecting partial reversion of the metabolic phenotype (phenoreversion) toward the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients, indicative of a reduction in the adaptive immune activity that has been previously detected in active SARS-CoV-2 infection. Other systemic inflammatory biomarkers such as GlycA and the kynurenine/tryptophan ratio remained elevated in some, but not all, patients. Correlation analysis, principal component analysis (PCA), and orthogonal-partial least-squares discriminant analysis (O-PLS-DA) showed that the follow-up patients were, as a group, metabolically distinct from controls and partially comapped with the acute-phase patients. Significant systematic metabolic differences between asymptomatic and symptomatic follow-up patients were also observed for multiple metabolites. The overall metabolic variance of the symptomatic patients was significantly greater than that of nonsymptomatic patients for multiple parameters (χ = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology, suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post-acute COVID-19 patients.
我们提出了一种多变量代谢分型方法，以评估非住院COVID-19患者的功能恢复情况以及“急性COVID-19综合征后”（俗称长期COVID）可能的生化后遗症。在急性COVID-19感染约3个月后采集患者的血液样本，并在6个月时进一步评估症状。约57%的患者有一个或多个持续症状，包括咳嗽、呼吸困难和流鼻涕等呼吸道相关症状，或慢性疲劳、嗅觉丧失、肌痛或关节疼痛等其他非呼吸道症状。使用核磁共振（NMR）光谱和质谱对血浆样本中的脂蛋白、糖蛋白、氨基酸、生物胺和色氨酸途径中间体进行定量分析。将随访患者（n = 27）的代谢数据与对照组（n = 41）和住院的严重急性呼吸综合征SARS-CoV-2阳性患者（n = 18，有多个时间点）进行比较。单变量和多变量统计显示功能恢复模式各异，许多患者表现出残留的COVID-19生物标志物特征。几个参数持续受到干扰，例如牛磺酸升高（与对照组相比，p = 3.6 × 10⁻³）和谷氨酰胺/谷氨酸比值降低（与对照组相比，p = 6.95 × 10⁻³），这表明可能存在肝脏和肌肉损伤以及与更广泛的组织修复或免疫功能相关的高能量需求。一些参数显示几乎完全正常化，例如血浆载脂蛋白B100/A1比值与健康对照组相似，但显著低于急性COVID-19后患者（p = 4.2 × 10⁻³），反映出代谢表型向健康代谢状态的部分逆转（表型逆转）。所有随访患者的血浆新蝶呤均正常化，这表明在活跃的SARS-CoV-2感染中先前检测到的适应性免疫活性降低。其他全身炎症生物标志物，如GlycA和犬尿氨酸/色氨酸比值，在一些但并非所有患者中仍然升高。相关性分析、主成分分析（PCA）和正交偏最小二乘判别分析（O-PLS-DA）表明，随访患者作为一个群体，在代谢上与对照组不同，并且部分与急性期患者重叠。对于多种代谢物，无症状和有症状的随访患者之间也观察到显著的系统性代谢差异。对于多个参数，有症状患者的总体代谢方差显著大于无症状患者（χ² = 0.014）。因此，包括患有急性COVID-19综合征后的患者在内的无症状随访患者表现出多种持续的生化病理生理学特征，这表明代谢分型方法可用于对个体急性COVID-19后患者进行多系统功能评估。
