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Systemic Perturbations in Amine and Kynurenine Metabolism Associated with Acute SARS-CoV-2 Infection and Inflammatory Cytokine Responses.
Lawler, NG, Gray, N, Kimhofer, T, Boughton, B, Gay, M, Yang, R, Morillon, AC, Chin, ST, Ryan, M, Begum, S, et al
Journal of proteome research. 2021;20(5):2796-2811
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Understanding the action of Covid-19 and the host response is paramount to developing personalised treatments and improving recovery rates. This cohort study of 64 individuals aimed to determine underlying biological signatures of individuals with severe and mild Covid-19, to potentially risk stratify patients and provide targeted treatments. The results showed that several biological signatures were disrupted with infection, some increased and some decreased and indicated possible liver, brain, and inflammatory disruptions. There was also evidence of a time-based pattern of biological disruptions, which may be of significance when looking at “long Covid” syndrome. It was concluded that identifying the hosts biological response to the virus offers insights into the viral action on the body. The action of Covid-19 on processes in the brain may indicate a secondary effect of the virus. Using biological markers to predict recovery of individuals suffering from “long Covid” may also be a possibility. This study could be used by healthcare professionals to understand which biological processes may be disrupted during Covid-19 infection, with the view to testing to understand who may be at risk of long-term complications post recovery.
Abstract
We performed quantitative metabolic phenotyping of blood plasma in parallel with cytokine/chemokine analysis from participants who were either SARS-CoV-2 (+) (n = 10) or SARS-CoV-2 (-) (n = 49). SARS-CoV-2 positivity was associated with a unique metabolic phenotype and demonstrated a complex systemic response to infection, including severe perturbations in amino acid and kynurenine metabolic pathways. Nine metabolites were elevated in plasma and strongly associated with infection (quinolinic acid, glutamic acid, nicotinic acid, aspartic acid, neopterin, kynurenine, phenylalanine, 3-hydroxykynurenine, and taurine; p < 0.05), while four metabolites were lower in infection (tryptophan, histidine, indole-3-acetic acid, and citrulline; p < 0.05). This signature supports a systemic metabolic phenoconversion following infection, indicating possible neurotoxicity and neurological disruption (elevations of 3-hydroxykynurenine and quinolinic acid) and liver dysfunction (reduction in Fischer's ratio and elevation of taurine). Finally, we report correlations between the key metabolite changes observed in the disease with concentrations of proinflammatory cytokines and chemokines showing strong immunometabolic disorder in response to SARS-CoV-2 infection.
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Vasculitis changes in COVID-19 survivors with persistent symptoms: an [18F]FDG-PET/CT study.
Sollini, M, Ciccarelli, M, Cecconi, M, Aghemo, A, Morelli, P, Gelardi, F, Chiti, A
European journal of nuclear medicine and molecular imaging. 2021;48(5):1460-1466
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The SARS-CoV-2 infection manifests with a broad spectrum of clinical patterns ranging from minimally or asymptomatic cases to mild illness, to severe infection, to critical disease. The aim of this study was to evaluate whether the radiopharmaceutical, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG), was able to demonstrate a persistent inflammatory process in the vascular epithelium or in any other site. The study included Covid-19 patients who recovered but complained of unexplained persisting symptoms for more than 30 days during the follow-up visits. The patients where divided into two groups; the long Covid and control group. Results indicate that although the total vascular score was similar in the two groups, the target-to-blood pool ratio was significantly higher in three vascular regions (thoracic aorta, right iliac artery, and femoral arteries) in the long Covid than in controls. Authors conclude that their findings suggest that SARS-CoV-2 induces vascular inflammation, which may be responsible for persisting symptoms.
Abstract
PURPOSE Several patients experience unexplained persistent symptoms after SARS-CoV-2 recovering. We aimed at evaluating if 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) was able to demonstrate a persistent inflammatory process. METHODS Recovered adult COVID-19 patients, who complained unexplained persisting symptoms for more than 30 days during the follow-up visits, were invited to participate in the study. Patients fulfilling inclusion criteria were imaged by [18F]FDG positron emission tomography/computed tomography ([18F]FDG-PET/CT). Whole-body [18F]FDG-PET/CT, performed according to good clinical practice, was qualitatively (comparison with background/liver) and semi-quantitatively (target-to-blood pool ratio calculated as average SUVmax artery/average SUVmean inferior vena cava) analyzed. Negative follow-up [18F]FDG-PET/CT images of oncologic patients matched for age/sex served as controls. Mann-Whitney test was used to test differences between groups. SPSS version 26 was used for analyses. RESULTS Ten recovered SARS-CoV-2 patients (seven male and three females, median age 52 years, range 46-80) with persisting symptoms were enrolled in the study. Common findings at visual analysis were increased [18F]FDG uptake in bone marrow and blood vessels (8/10 and 6/10 cases, respectively). [18F]FDG uptake in bone marrow did not differ between cases and controls (p = 0.16). The total vascular score was similar in the two groups (p = 0.95). The target-to-blood pool ratio resulted higher in recovered SARS-CoV-2 patients than in controls. CONCLUSION Although the total vascular score was similar in the two groups, the target-to-blood pool ratio was significantly higher in three vascular regions (thoracic aorta, right iliac artery, and femoral arteries) in the recovered COVID-19 cohort than in controls, suggesting that SARS-CoV-2 induces vascular inflammation, which may be responsible for persisting symptoms.
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Understanding Viral Infection Mechanisms and Patient Symptoms for the Development of COVID-19 Therapeutics.
Choi, HM, Moon, SY, Yang, HI, Kim, KS
International journal of molecular sciences. 2021;22(4)
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The outbreak of a novel coronavirus was reported in Wuhan, in the Hubei province of China, in December 2019. This virus was officially designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) because of its phylogenetic and taxonomic similarities to other coronaviruses. The aim of this review was to understand the viral infection mechanisms of SARS-CoV-2, the clinical features of Covid-19 and the mechanisms through which Covid-19 can be effectively treated with existing drugs. Literature shows that: • SARS-CoV-2 is usually transmitted by inhalation or contact with infected droplets. Inhaled droplets or aerosol carrying the virus then infect and spread through the respiratory tracts. • Severe inflammatory response is a remarkable feature of Covid-19 symptoms. This is caused by delayed viral clearance, which induces chronic systemic inflammation and widespread tissue damage, even leading to cytokine storms. • The incubation period is generally 5-6 days, but it ranges from one day to as much as two weeks. • Interstitial pneumonia and subsequent acute respiratory distress syndrome are the leading causes of death in patients with Covid-19. • There is no licensed treatment for Covid-19, only a combination of antiviral and anti-inflammatory drug treatments are being used. Authors conclude that their finding may provide new insights into the development of therapeutics by understanding the various clinical and basic research studies currently underway.
Abstract
Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has become a worldwide pandemic. Symptoms range from mild fever to cough, fatigue, severe pneumonia, acute respiratory distress syndrome (ARDS), and organ failure, with a mortality rate of 2.2%. However, there are no licensed drugs or definitive treatment strategies for patients with severe COVID-19. Only antiviral or anti-inflammatory drugs are used as symptomatic treatments based on clinician experience. Basic medical researchers are also trying to develop COVID-19 therapeutics. However, there is limited systematic information about the pathogenesis of COVID-19 symptoms that cause tissue damage or death and the mechanisms by which the virus infects and replicates in cells. Here, we introduce recent knowledge of time course changes in viral titers, delayed virus clearance, and persistent systemic inflammation in patients with severe COVID-19. Based on the concept of drug reposition, we review which antiviral or anti-inflammatory drugs can effectively treat COVID-19 patients based on progressive symptoms and the mechanisms inhibiting virus infection and replication.
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The potential long-term impact of the COVID-19 outbreak on patients with non-communicable diseases in Europe: consequences for healthy ageing.
Palmer, K, Monaco, A, Kivipelto, M, Onder, G, Maggi, S, Michel, JP, Prieto, R, Sykara, G, Donde, S
Aging clinical and experimental research. 2020;32(7):1189-1194
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Individuals with non-communicable diseases (NCD's), i.e. diseases that are not transmitted from person to person, such as diabetes and heart disease, are at a much higher risk of death from Covid-19. But for individuals who contract Covid-19 and survive, there could be considerable implications on the progression of their pre-existing condition. This review study aimed to discuss how the Covid-19 pandemic might impact management and outcomes in individuals with NCD's. The paper outlined that higher Covid-19 death rates in individuals with NCD's, will cause a decline of these diseases within populations. Although there is little peer reviewed research to support this, circumstantial reports are already suggesting lower hospital admissions for stroke and heart attacks. However it should be noted that it is obvious that this paper was written at the start of the pandemic. The paper went on to discuss that the pandemic and subsequent government actions to control the infection will affect individuals with NCD's through reductions in physical activity, social interaction, and vitamin D intake. Changes to medical management, the subsequent possibility of decreased adherence to medications and the halting of much needed research on NCD's in favour of Covid-19 research, will further exacerbate the impact on individuals with pre-existing conditions. Finally, areas upon which the healthcare system and government should be focusing in order to help individuals with NCD's were discussed. Amongst these was the acknowledgement that the public and private healthcare systems have collaborated with success and this should continue and that on-going support through technology such as Telehealth services and patient advocacy associations is a necessity. Clinicians could use this paper to understand how Covid-19 could accelerate disease progression in individuals with NCD’s and that close monitoring is essential. For individuals with NCD’s who do not have Covid-19, close monitoring would still be required to ensure that government strategies to contain the virus do not exacerbate their condition.
Abstract
The early stages of the COVID-19 pandemic have focused on containing SARS-CoV-2 infection and identifying treatment strategies. While controlling this communicable disease is of utmost importance, the long-term effect on individuals with non-communicable diseases (NCD) is significant. Although certain NCDs appear to increase the severity of COVID-19 and mortality risk, SARS-CoV-2 infection in survivors with NCDs may also affect the progression of their pre-existing clinical conditions. Infection containment measures will have substantial short- and long-term consequences; social distancing and quarantine restrictions will reduce physical activity and increase other unhealthy lifestyles, thus increasing NCD risk factors and worsening clinical symptoms. Vitamin D levels might decrease and there might be a rise in mental health disorders. Many countries have made changes to routine management of NCD patients, e.g., cancelling non-urgent outpatient visits, which will have important implications for NCD management, diagnosis of new-onset NCDs, medication adherence, and NCD progression. We may have opportunities to learn from this unprecedented crisis on how to leverage healthcare technologies and improve procedures to optimize healthcare service provision. This article discusses how the COVID-19 outbreak and related infection control measures could hit the most frail individuals, worsening the condition of NCD patients, while further jeopardizing the sustainability of the healthcare systems. We suggest ways to define an integrated strategy that could involve both public institutional entities and the private sector to safeguard frail individuals and mitigate the impact of the outbreak.
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Endocrine and metabolic aspects of the COVID-19 pandemic.
Marazuela, M, Giustina, A, Puig-Domingo, M
Reviews in endocrine & metabolic disorders. 2020;21(4):495-507
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Endocrine and metabolic related diseases such as diabetes and obesity may increase the risk of developing severe Covid-19 and as a result these diseases could be severely affected by Covid-19 infection. This very large review paper looked at over 100 studies and outlined the interrelationship between Covid-19 infection and several endocrine diseases. Diabetes, obesity, pituitary-hypothalamic function, thyroid function, Cushing's syndrome and adrenal function were all reviewed. No aim was stated. Data on individuals with obesity and diabetes indicated an increased risk for severe Covid-19 infection, hospitalisation and mortality. Data surrounding pituitary-hypothalamic function, thyroid function, Cushing's syndrome and adrenal function was less abundant, however neurological issues in Covid-19 patients suggested an involvement of the pituitary and hypothalamus. In lieu of sufficient data the author commented on the possible similarities between severe acute respiratory syndrome coronavirus with the Covid-19 virus. A number of management strategies were discussed such as the use of vitamin D, oxytocin and melatonin, however the authors commented on the lack of data regarding oxytocin and melatonin in Covid-19 patients, but mechanistic data suggested they might be of use. No overall conclusions were drawn on the findings. Clinicians could use this paper to understand how patients with pre-existing endocrine and metabolic conditions may be at a higher risk of more severe Covid-19 and if contracted could exacerbate their pre-existing condition. These patients could require constant monitoring and additional measures to avoid contracting Covid-19. Supplements such as vitamin D, oxytocin or melatonin could be therapeutic, however more data needs to be reviewed.
Abstract
COVID-19 infection has tremendously impacted our daily clinical practice as well as our social living organization. Virtually all organs and biological systems suffer from this new coronavirus infection, either because the virus targets directly specific tissues or because of indirect effects. Endocrine diseases are not an exception and some of endocrine organs are at risk of direct or indirect lesion by COVID-19. Although there is still no evidence of higher predisposition to contract the infection in patients with diabetes and/or obesity, the coexistence of these conditions contributes to a worse prognosis because both conditions confer an impaired immunologic system. Cytokines storm can be amplified by these two latter conditions thereby leading to multisystemic failure and death. Glycaemic control has been demonstrated to be crucial to avoiding long hospital stays, ICU requirement and also prevention of excessive mortality. Endocrine treatment modifications as a consequence of COVID-19 infection are required in a proactive manner, in order to avoid decompensation and eventual hospital admission. This is the case of diabetes and adrenal insufficiency in which prompt increase of insulin dosage and substitutive adrenal steroids through adoption of the sick day's rules should be warranted, as well as easy contact with the health care provider through telematic different modalities. New possible endocrinological targets of COVID-19 have been recently described and warrant a full study in the next future.
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Coronavirus disease 2019 (COVID-19) and obesity. Impact of obesity and its main comorbidities in the evolution of the disease.
Cornejo-Pareja, IM, Gómez-Pérez, AM, Fernández-García, JC, Barahona San Millan, R, Aguilera Luque, A, de Hollanda, A, Jiménez, A, Jimenez-Murcia, S, Munguia, L, Ortega, E, et al
European eating disorders review : the journal of the Eating Disorders Association. 2020;28(6):799-815
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The Covid-19 pandemic has caused thousands of deaths worldwide. Being obese is associated with worse outcomes following infection with Covid-19. This review aimed to summarise the data available on the relationship between Covid-19 and obesity, and explored some of the possible reasons for this relationship. The researchers found that obesity is an independent and strong risk factor for severe infection, Intensive Care Unit (ICU) admission and death. The impact of obesity might be of particular relevance in males and in younger individuals. Long‐term complications of Covid‐19 could also be more frequent and severe in obese subjects. There are many potential mechanisms that could explain this relationship. These include the effects of obesity and related diseases such as diabetes, high blood pressure and heart disease on the immune system, lung function, vitamin D deficiency and male hormones. The researchers also discussed the possibility of fat cells acting as a possible reservoir for Covid-19 infection. Research into Covid-19 is still at a very early stage and more studies are needed.
Abstract
The COVID-19 pandemic is posing a great challenge worldwide. Its rapid progression has caused thousands of deaths worldwide. Although multiple aspects remain to be clarified, some risk factors associated with a worse prognosis have been identified. These include obesity and some of its main complications, such as diabetes and high blood pressure. Furthermore, although the possible long-term complications and psychological effects that may appear in survivors of COVID-19 are not well known yet, there is a concern that those complications may be greater in obese patients. In this manuscript, we review some of the data published so far and the main points that remain to be elucidated are emphasized.
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The Functional Medicine Approach to COVID-19: Virus-Specific Nutraceutical and Botanical Agents.
Evans, JM, Luby, R, Lukaczer, D, Rountree, R, Stone, PM, Guilliams, TG, Yanuck, S, Messier, H, Ramsdell, K, Hanaway, PJ
Integrative medicine (Encinitas, Calif.). 2020;19(Suppl 1):34-42
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The practice of Functional Medicine, with respect to interventions, emphasizes the primacy of safety, validity, and effectiveness. Data for the effectiveness of interventions targeting the viral mechanisms of Covid-19 are nascent and rapidly emerging. The aim of this review was to assess the scientific plausibility of promising prevention approaches and therapeutic (nutraceutical and botanical) interventions and suggest clinical recommendations. A coronavirus such as SARS-CoV-2 can be deadly because of its ability to stimulate a part of the innate immune response called the inflammasome. This can cause uncontrolled release of pro-inflammatory cytokines, leading to cytokine storm and severe, sometimes irreversible, damage to respiratory epithelium. In order to prevent the activation of a particular inflammasome the following compounds are being recommended; quercetin, curcumin, epigallocatechin gallate, n-acetylcysteine, resveratrol, vitamin D, vitamin A, vitamin C, elderberry, melatonin, zinc and palmitoylethanolamide. Authors emphasise that the recommendations are meant to identify botanical and nutraceutical agents that may boost the immune system and not as a means of treatment.
Abstract
As the novel infection with SARS-CoV-2 emerges, objective assessment of the scientific plausibility of nutraceutical and botanical interventions for prevention and treatment is important. We evaluate twelve such interventions with mechanisms of action that modulate the immune system, impair viral replication, and/or have been demonstrated to reduce severity of illness. These are examples of interventions that, mechanistically, can help protect patients in the presence of the prevalent and infectious SARS-CoV-2 virus. While there are limited studies to validate these agents to specifically prevent COVID-19, they have been chosen based upon their level of evidence for effectiveness and safety profiles, in the context of other viral infections. These agents are to be used in a patient-specific manner in concert with lifestyle interventions known to strengthen immune response (see related article in this issue of IMCJ).