Predictive Metabolome of Long-Term Outcome in COVID-19
Those who recover from COVID-19, especially after severe cases, have experienced a great deal of pain and discomfort. However, because of potential multi-organ injuries that more closely resemble the situation after sepsis rather than recovery from an Influenza virus infection, COVID-19 survivors often experience long-term consequences of the infection.
For many patients, even after viral clearance, the road to recovery is far from over. For some, these complications are as mild as the inability to smell or taste, while those who are less fortunate can experience lasting respiratory problems, cardiovascular complications or new onset of metabolic disorders.
In this article, we will discuss selected long-term health challenges associated with COVID-19, as well as the metabolic processes that may be associated. We will furthermore highlight the potential to address these challenges through metabolomic research.
Recent work has revealed associations between COVID-19 and new onset metabolic syndrome, diabetes and changes in the vasculature. This may ultimately contribute to an increased risk for stroke and cardiovascular disease. Moreover, it has been suggested that the elevated risk for diabetes in COVID-19 survivors may be due to a deterioration of metabolic control and direct damage to pancreatic beta cells caused by the virus (Apicella et al., 2020).
It may be unsurprising that COVID-19 has a significant and sustained impact on metabolic homeostasis, given that a long-term follow up study on survivors of the 2002/2003 SARS outbreak found that 50 % of patients lacking a history of Type 2 diabetes (T2D) developed it during the infection. Furthermore, 5 % of cases persisted for an extended period of time. The onset of infection-induced T2D in these patients was accompanied by dysregulated glucose metabolism, hyperlipidemia, and cardiovascular abnormalities, as well as changes in lysophosphatidylcholines and lysophosphatidylinositol. (Wu et al., 2017).
In addition to the direct impact of COVID-19, intensive care is associated with additional health challenges. It is well established that intensive care patients with acute respiratory distress experience dramatic weight loss. While these patients demonstrate rapid recovery back to a normal weight, they tend to gain adipose tissue rather than regaining lean body mass, thereby adding to the risk of cardiometabolic disease. (Chan et al., 2018)
Metabolomics is an attractive technology for assessing and monitoring cardiometabolic risk factors associated with the long-term health impact of SARS-CoV-2 infections. For example, established biomarkers of prediabetes (Wang-Sattler et al., 2012) and the transition from gestational diabetes to T2D (Wheeler et al., 2020) may also aid in determining the risk of diabetes resulting from infection-mediated metabolic dysregulation. In either of the cited cases, the predictive biomarker signatures are multi-factorial. They cover various aspects of the pathophysiology, such as altered glucose metabolism, abnormalities in lipid homeostasis and the metabolism of branched-chain amino acids, as well as perturbations in mitochondrial dynamics. Besides predicting the risk of diabetes, metabolomic signatures have also been helpful in analyzing frailty (Westbrook et al., 2016; Corona et al., 2014) and muscle quality (Moaddel et al., 2016). Moreover, nitric oxide metabolism and arachidonic acid metabolism are two metabolic processes closely related with angiogenesis and immune regulation, thus providing a link between the hyper-inflammatory status during infection and the risk of vascular disease. Thus, such markers may serve as a window into the future, revealing the health status that a patient will achieve upon recovery from COVID-19, and providing a rationale for supportive care.
It has been suggested that COVID-19 patients are at greater risk for a range of neuropsychiatric outcomes, including stroke, impaired cognitive function, depression and post-traumatic stress disorder (Varatharaj et al., 2020).
The increased risk of stroke may stem from dysregulation in the coagulation cascade, which could result in bleeding as well as thrombotic events. As tryptophan metabolism is involved in regulating coagulation (Pawlak et al., 2009), this pathway may be valuable for evaluating the risk of stroke. As previously discussed, metabolic dysregulations observed in metabolic syndrome constitute a risk factor for vascular events. especiallycerebrovascular ones, as metabolism is crucial for maintaining healthy blood vessels and facilitating angiogenesis (Draoui et al., 2017).
Extensive studies on Alzheimer’s Disease and Parkinson’s Disease have shown that metabolic parameters exhibit a clear relationship with different components of brain pathology and a good correlation with cognitive scores. In addition, metabolomics has been used in the context of traumatic brain injury (Fiandaca et al., 2018), as well as Huntington’s disease (Graham et al., 2018), which is characterized by a severe inflammatory state, similar to that observed in COVID-19. These studies prove the utility of metabolomics as a minimally-invasive tool for monitoring cognitive and CNS function by means of a small blood sample analysis.
Finally, mental trauma, as from intensive care stress, can have long-term metabolic consequences (Boeck et al., 2016). Depression is increasingly being understood as a disorder that involves inflammatory and bioenergetic components. Metabolomics has shown promise in monitoring pharmaceutical (Cysz et al., 2019) as well as cognitive behavioral therapy (Bhattacharyya et al., 2019) for depression.
Other health challenges
Some COVID-19 survivors, particularly following a severe disease course, suffer from a persistently impaired lung function. In this context, it is noteworthy that cholesterol metabolites are involved in local immune regulation in the lung (Gowdy & Fessler, 2012), which may give them prognostic value regarding the recovery from lung injury. ADMA (Asymmetric Dimethylarginine), a biomarker associated with proteolysis, has been shown to be a strong predictor of long-term outcome in COPD (Vögeli et al., 2017) and thus, may similarly predict long term lung functional outcomes following COVID-19.
Impaired kidney function may be a complication of COVID-19 infections, and kidney damage is being investigated as a potential side effect of Remdesivir treatment (Xu et al., 2020). A number of metabolites have been suggested or are currently in clinical use as biomarkers for impaired kidney function, including creatinine and SDMA (Symmetric Dimethylarginine). The latter, as ADMA, is associated with proteolysis, but relies on renal clearance, thus accumulating when the kidney function is impaired.
COVID-19 is a multifactorial disease with a wide range of pathophysiological processes implicated in defining long-term outcomes. Metabolomics, by profiling of hundreds of metabolites, can inform on many of the involved processes, thus providing a means to better understand the long-term impact of this novel disease.
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