Bruker’s Molecular Phenomics Research Tools Enable New Insights into ‘Long COVID’ and Post-Acute Metabolic Abnormalities

PERTH, Western Australia – May 20th, 2021: A clinical research collaboration on COVID-19 pheno-conversion and subsequent pheno-reversion has discovered transient and persistent systemic changes of the molecular signatures in patient blood samples three months after the acute COVID-19 disease phase. These biochemical abnormalities, identified by a quantitative, label-free assay platform integrating nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), relate to ongoing ‘long COVID’ symptoms, which persist post-acute infection and can affect more than half of the recovered COVID patients - even six months after infection.

A series of seminal papers on the molecular phenome of acute disease and post-acute COVID syndrome in patient plasma has been announced (https://medicalxpress.com/news/2021-05-covid-affecting-patients-months.html) and published (1-5) by the Australian National Phenome Centre (ANPC) at Murdoch University, in collaboration with other academic medical centers, and with Bruker Corporation (Nasdaq: BRKR) as a key technology partner.

综合定量NMR和MS分析平台form, which is for research use only, has revealed metabolic abnormalities, interactions of metabolic markers with cytokines, as well as interactions of lipoproteins with inflammation markers, caused by acute COVID-19. It enabled the creation of a multi-assay panel of pheno-conversion markers that change significantly during disease progression. This molecular phenomics panel can now also provide a measure of a patient’s partial recovery, or of emerging chronic PACS risks, e.g., for new-onset diabetes or for new-onset atherosclerosis, and for other persistent or reoccurring symptoms, including chronic fatigue, ‘brain fog’ and numerous other reported long COVID symptoms.

Post-acute follow up studies on non-hospitalized and mildly affected COVID-19 patients revealed that the majority of these patients is not back to normal health or normal biochemistry three months on and suffers from PACS, also referred to as ‘Long COVID’, characterized by persistent symptoms and health dysfunction after the acute infection. More than 57% of these patients show one or more symptoms up to six months following the acute phase, and many of them have metabolic abnormalities as revealed by the NMR and MS based pheno-reversion panel.

Professor Jeremy Nicholson, Pro Vice Chancellor for the Health Futures Institute at Murdoch University and Director of the ANPC explained: “Advanced NMR- and MS-screening of blood plasma provides complementary insights into the complex COVID-19 systemic pattern. There were multiple but variable biochemical abnormalities in the follow up patients with a variety of partial recovery phenotypes. We noted that most of the follow up COVID-19 patients had metabolic abnormalities irrespective of whether they were still symptomatic, but symptomatic patients were statistically more likely to have biochemical abnormalities.”
He continued: “This is an immensely dangerous disease that is not only costing lives today, but as we’re discovering now, may have serious health consequences for some patients long into the future, even in relatively mild original cases.”

急性阶段三个月的大多数患者在六个月时有症状和无症状的症状异常有多种血液代谢异常。研究人员发现，在感染期间，Covid-19患者血液中的血浆脂蛋白发生了变化，并且更接近糖尿病和动脉粥样硬化患者通常发现的模式。随访患者中有些异常降低，是可逆的，而与肝脏，能量代谢和神经病理学有关的标记通常并未完全反转。

The latest research is consistent with earlier findings from the ANPC that showed COVID-19 is a systemic disease with multi-organ effects. The concept of pheno-conversion, as expressed in the lipoprotein and metabolic profile of blood plasma, establishes molecular phenotype biomarkers that can be analyzed for disease progression, severity and treatment. This underlines the importance of longitudinal studies on recovered patients for PACS effects and long-term health risks.

ANPC also devised a novel relaxation and diffusion edited NMR method that refined selectivity and led to the discovery of novel phospholipid signals from supramolecular clusters (3). “This is the first example of motional editing of complex blood plasma spectra to enhance the selectivity of a diagnostic procedure and opens the door to other NMR approaches to classification based on the dynamics of molecules, as well as on concentrations,” added Professor Nicholson.

Bruker Biospin的Applied，Industrial and Clinical部门的CTO Manf必威东盟体育red Spraul博士评论说：“这些发现强调了我们集成的NMR和MS Assay平台对PAC的风险筛查的潜力。我们的研究方法对于个性化的分子现象特征是可靠的，并且可以转移，从而为更好地理解Covid-19的长期影响提供了一个门户。这些分子表型的见解最终有望支持更好的急性后Covid-19患者管理，以更快地康复，并降低了医疗保健成本。”

通过NMR和MS分析，检测到COVID-19的现场转化和势逆转录特征，为心脏病学，代谢，糖尿病，肾脏疾病，肝功能，神经系统作用和炎症的潜在生物标志物提供了互补的见解。

Bruker has begun validation of this integrated NMR/MS clinical research assay set in Europe, with the goal of developing PACS personalized risk screening and longitudinal patient monitoring diagnostic methods.

Dr. Óscar Millet, Principal Investigator atCIC bioGUNE in Bilbao, Spain, commented: “As one of the key clinical research labs for precision medicine in Europe, we see huge potential for the PACS research enabled by high performance NMR and MS technology. We are an active member of the International COVID-19 research network, which is led by the ANPC. The harmonized research approach, which is based on standardized operating procedures developed by ANPC and Bruker, has allowed us to study PACS on Spanish patient cohorts and cross-validate our data with those of the ANPC at both the analytical and biological level.”

The studies were conducted using Avance™ IVDr NMR 600 MHz spectrometers integrated in the ANPC class II biosecurity laboratory, together with Bruker and CIC bioGUNE in-vitro diagnostics NMR research (IVDr) technology methods. The ANPC has also equipped its molecular phenomics lab with state-of-the-art mass spectrometers, including Bruker impact II and timsTOF™ Pro QTOF-MS, and a solariX™ MRMS system.

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1. Kimhofer T，Lodge S，Whiley L等。定量血浆脂蛋白，代谢和氨基酸数据的整合建模揭示了SARS-COV −2感染的多器官病理学特征，蛋白质组Res 2020 11月6;19(11):4442-4454
2. Lodge S, Nitschke P, Kimhofer T, et al. NMR Spectroscopic Windows on the Systemic Effects of SARS-CoV-2 Infection on Plasma Lipoproteins and Metabolites in Relation to Circulating Cytokines.蛋白酶研究杂志，2020年。20 1382-1396。https://pubs.acs.org/doi/10.1021/acs.jproteome.0c00876
3. Lodge S, Nitschke P, Kimhofer T, et al. Diffusion- and Relaxation-Edited Proton NMR Spectroscopy of 2 Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature 3 of SARS-CoV‐2 Infection Analytical Chemistry, 2021.https://dx.doi.org/10.1021/acs.analchem.0c04952
4. Nathan G. Lawler et al. Systemic Perturbations in Amine and Kynurenine Metabolism Associated with Acute SARS-CoV-2 Infection and Inflammatory Cytokine Responses, Journal of Proteome Research (March 16, 2021).doi：10.1021/acs.jproteome.1c00052
5. Elaine Holmes, Julien Wist, 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, Journal of Proteome Research (May 19, 2021).https://pubs.acs.org/doi/10.1021/acs.jproteome.1c00224

This research was funded by the Spinnaker Health Research Foundation, The McCusker Foundation and the Western Australian State Government